Eculizumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Soliris: 300 mg/30 mL (30 mL) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Eculizumab is a humanized monoclonal IgG antibody that binds to complement protein C5, preventing cleavage into C5a and C5b. Blocking the formation of C5b inhibits the subsequent formation of terminal complex C5b-9 or MAC. Terminal complement-mediated intravascular hemolysis is a key clinical feature of paroxysmal nocturnal hemoglobinuria (PNH); blocking the formation of membrane attack complex (MAC) results in stabilization of hemoglobin and a reduction in the need for RBC transfusions. Impairment of complement activity regulation leads to uncontrolled complement activation in atypical hemolytic uremic syndrome (aHUS).

Pharmacokinetics/Pharmacodynamics

Distribution

5 to 8 L

Onset of Action

PNH: Reduced hemolysis: ≤1 week

Half-Life Elimination

~270 to 414 hours (during plasma exchange the half-life is reduced to 1.26 hours)

Use: Labeled Indications

Atypical hemolytic uremic syndrome: Treatment of atypical hemolytic uremic syndrome to inhibit complement-mediated thrombotic microangiopathy.

Limitation of use: Eculizumab is not indicated for the treatment of patients with Shiga toxin Escherichia coli-related hemolytic uremic syndrome.

Generalized myasthenia gravis, refractory: Treatment of refractory generalized myasthenia gravis in adults who are antiacetylcholine receptor antibody positive.

Neuromyelitis optica spectrum disorder: Treatment of neuromyelitis optica spectrum disorder in adults who are aquaporin-4-antibody positive.

Paroxysmal nocturnal hemoglobinuria: Treatment of paroxysmal nocturnal hemoglobinuria to reduce hemolysis.

Contraindications

US labeling: Unresolved serious Neisseria meningitidis infection; patients not currently vaccinated against Neisseria meningitidis (unless risks of treatment delay outweigh risk of developing a meningococcal infection)

Canadian labeling: Hypersensitivity to eculizumab, murine proteins, or any component of the formulation; unresolved Neisseria meningitidis infection; patients not currently vaccinated against Neisseria meningitidis (unless receiving appropriate prophylactic antibiotic treatment until 2 weeks after vaccination)

Dosage and Administration

Dosing: Adult

Note: Patients must receive meningococcal vaccine at least 2 weeks prior to treatment initiation; revaccinate according to current guidelines. If urgent eculizumab initiation is necessary and <2 weeks after vaccination, provide 2 weeks of antibacterial prophylaxis; in unvaccinated patients, administer meningococcal vaccine as soon as possible and provide 2 weeks of antibacterial prophylaxis. To reduce the risk for meningococcal disease, consider antimicrobial prophylaxis with oral antibiotics (penicillin, or macrolides if penicillin-allergic) for the duration of eculizumab therapy (McNamara 2017). Administer eculizumab at the recommended time interval or within 2 days of the interval.

Atypical hemolytic uremic syndrome: IV: Induction: 900 mg weekly for 4 doses; Maintenance: 1,200 mg at week 5, then 1,200 mg every 2 weeks thereafter.

Supplemental dosing for patients receiving plasmapheresis or plasma exchange:

If most recent dose was ≥600 mg, administer 600 mg within 60 minutes after each plasmapheresis or plasma exchange.

If most recent dose was 300 mg, administer 300 mg within 60 minutes after each plasmapheresis or plasma exchange.

Supplemental dosing for patients receiving fresh frozen plasma infusion: If most recent dose was ≥300 mg, administer 300 mg within 60 minutes prior to each infusion of fresh frozen plasma.

Generalized myasthenia gravis, refractory: IV: Induction: 900 mg weekly for 4 doses; Maintenance: 1,200 mg at week 5, then 1,200 mg every 2 weeks thereafter.

Supplemental dosing for patients receiving plasmapheresis or plasma exchange:

If most recent dose was ≥600 mg, administer 600 mg within 60 minutes after each plasmapheresis or plasma exchange.

If most recent dose was 300 mg, administer 300 mg within 60 minutes after each plasmapheresis or plasma exchange.

Supplemental dosing for patients receiving fresh frozen plasma infusion: If most recent dose was ≥300 mg, administer 300 mg within 60 minutes prior to each infusion of fresh frozen plasma.

Neuromyelitis optica spectrum disorder: IV: Induction: 900 mg weekly for 4 doses; Maintenance: 1,200 mg at week 5, then 1,200 mg every 2 weeks thereafter.

Supplemental dosing for patients receiving plasmapheresis or plasma exchange:

If most recent dose was ≥600 mg, administer 600 mg within 60 minutes after each plasmapheresis or plasma exchange.

If most recent dose was 300 mg, administer 300 mg within 60 minutes after each plasmapheresis or plasma exchange.

Supplemental dosing for patients receiving fresh frozen plasma infusion: If most recent dose was ≥300 mg, administer 300 mg within 60 minutes prior to each infusion of fresh frozen plasma.

Paroxysmal nocturnal hemoglobinuria: IV: Induction: 600 mg weekly for 4 doses; Maintenance: 900 mg at week 5; then 900 mg every 2 weeks thereafter.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Patients must receive meningococcal vaccine at least 2 weeks prior to treatment initiation; if the risk of treatment delay outweighs the risk of developing meningococcal infection then administer vaccine as soon as possible. Revaccinate according to current guidelines with consideration of eculizumab therapy duration. Treatment should be administered at the recommended time interval although administration may be varied by ± 2 days.

Atypical hemolytic uremic syndrome (aHUS): Infants, Children, and Adolescents: IV:

Patient weight:

5 kg to <10 kg: Induction: 300 mg weekly for 1 dose; Maintenance: 300 mg at week 2, then 300 mg every 3 weeks

10 kg to <20 kg: Induction: 600 mg weekly for 1 dose; Maintenance: 300 mg at week 2, then 300 mg every 2 weeks

20 kg to <30 kg: Induction: 600 mg weekly for 2 doses; Maintenance: 600 mg at week 3, then 600 mg every 2 weeks

30 kg to <40 kg: Induction: 600 mg weekly for 2 doses; Maintenance: 900 mg at week 3, then 900 mg every 2 weeks

≥40 kg: Induction: 900 mg weekly for 4 doses; Maintenance: 1,200 mg at week 5, then 1,200 mg every 2 weeks

Supplemental dosing for patients receiving plasmapheresis or plasma exchange:

If most recent dose was 300 mg, administer 300 mg within 60 minutes after each plasmapheresis or plasma exchange

If most recent dose was ≥600 mg, administer 600 mg within 60 minutes after each plasmapheresis or plasma exchange

Supplemental dosing for patients receiving fresh frozen plasma infusion: If most recent dose was ≥300 mg, administer 300 mg within 60 minutes prior to each infusion of fresh frozen plasma

Reconstitution

Add eculizumab to an infusion bag and dilute with an equal volume of D5W, sodium chloride 0.9%, sodium chloride 0.45%, or Ringer's injection to a final concentration of 5 mg/mL (eg, 300 mg to a final volume of 60 mL, 600 mg to a final volume of 120 mL, 900 mg to a final volume of 180 mL, or 1,200 mg to a final volume of 240 mL). Gently invert bag to mix thoroughly; do not shake.

Administration

IV: Allow to reach room temperature prior to administration. Infuse over 35 minutes in adults and over 1 to 4 hours in pediatric patients; do not administer as an IV push or bolus. Decrease infusion rate or discontinue for infusion reactions; do not exceed a maximum 2-hour duration of infusion in adults. Monitor for at least 1 hour following completion of infusion (for signs/symptoms of infusion reaction).

Assess vaccination status prior to initiation; patients must receive meningococcal vaccine at least 2 weeks prior to treatment initiation. If eculizumab must be initiated urgently and less than 2 weeks after vaccination, provide 2 weeks of antibacterial prophylaxis; in unvaccinated patients, administer meningococcal vaccine as soon as possible and provide 2 weeks of antibacterial prophylaxis.

Storage

Prior to dilution, store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Vials may be stored in the original carton at not more than 25°C (77°F) for only a single period up to 3 days. Protect from light; do not shake. Following dilution, store at room temperature or refrigerate; use within 24 hours. If refrigerated, allow admixture to reach room temperature prior to administration (do not use a heat source for warming).

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Meningococcal Group B Vaccine: Eculizumab may diminish the therapeutic effect of Meningococcal Group B Vaccine. Meningococcal Group B Vaccine may diminish the therapeutic effect of Eculizumab. The meningococcal vaccine may result in increased complement activation, possibly worsening the symptoms of any underlying complement-mediated diseases, such as hemolysis and anemia. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Hypertension (adolescents and adults: 17% to 59%; infants and children: 22%), tachycardia (infants and children: 40%; children: 20%), peripheral edema (adolescents and adults: 20% to 29%; adults: 8%), hypotension (adolescents and adults: 12% to 20%)

Central nervous system: Headache (adolescents and adults: 37% to 50%; infants and children: 17%), insomnia (adolescents and adults: 10% to 24%), fatigue (adolescents and adults: 7% to 20%), dizziness (adults: 15%)

Dermatologic: Skin rash (12% to 22%), pruritus (adolescents and adults: 6% to 15%)

Endocrine & metabolic: Hypokalemia (adolescents and adults: 10% to 18%)

Gastrointestinal: Diarrhea (16% to 47%), vomiting (10% to 47%), nausea (adolescents and adults: 12% to 40%), abdominal pain (8% to 33%), gastroenteritis (adolescents and adults: 5% to 20%)

Genitourinary: Urinary tract infection (adolescents and adults: 15% to 35%; infants and children: 17%), urinary tract symptoms (infants and children: 17%), proteinuria (adolescents and adults: 5% to 12%)

Hematologic & oncologic: Anemia (adolescents and adults: 17% to 35%), neoplasm (adolescents and adults: 6% to 30%), leukopenia (adolescents and adults: 5% to 24%)

Infection: Infection (adolescents and adults: 24%), influenza (adults: 11%)

Local: Catheter infection (infants and children: 17%)

Neuromuscular & skeletal: Asthenia (adolescents and adults: 5% to 20%), back pain (adolescents and adults: 5% to 19%), arthralgia (adolescents and adults: 6% to 17%), musculoskeletal pain (adults: 6% to 15%), muscle spasm (5% to 11%)

Ophthalmic: Eye disease (adolescents and adults: 10% to 29%; infants and children: 17%)

Renal: Renal insufficiency (adolescents and adults: 15% to 29%)

Respiratory: Cough (infants and children: 20% to 60%; adolescents and adults: 12% to 30%), nasopharyngitis (adolescents and adults: 17% to 55%; infants and children: 17%), nasal congestion (infants and children: 40%; children: 20%), upper respiratory tract infection (5% to 40%), rhinitis (infants and children: 22%), bronchitis (adolescents and adults: 9% to 18%)

Miscellaneous: Fever (infants and children: 40% to 80%; adolescents and adults: 17% to 25%; adults: 7%)

1% to 10%:

Cardiovascular: Severe hypertension (5% to 9%)

Central nervous system: High fever (infants and children: 9%), paresthesia (adults: 8%)

Dermatologic: Alopecia (adults: 5%), cellulitis (adults: 5%)

Gastrointestinal: Viral gastroenteritis (infants and children: 9%), constipation (adults: 7% to 9%), decreased appetite (adults: 5%)

Genitourinary: Cystitis (adults: 8%), chronic renal failure (adolescents and adults: 5%)

Hematologic & oncologic: Bruise (adults: 8% to 10%), lymphocytopenia (adults: 5%)

Immunologic: Antibody development (≤3%; neutralizing: 1%)

Infection: Herpes simplex infection (adults: 7% to 8%), meningococcal infection (1% to 2%)

Neuromuscular & skeletal: Limb pain (adults: 7%), myalgia (adults: 7%)

Ophthalmic: Conjunctivitis (adults: 9%), hordeolum (adults: 7%), cataract (adults: 6%)

Respiratory: Pharyngitis (adults: 10%), respiratory tract infection (adults: 7%), oropharyngeal pain (6% to 7%), sinusitis (adults: 6% to 7%), flu-like symptoms (adults: 5%)

<1%, postmarketing, and/or case reports: Aspergillosis, genitourinary infection, septic meningitis, systemic lupus erythematosus

Warnings/Precautions

Concerns related to adverse effects:

• Infections: Serious infections with Neisseria species (other than N. meningitides), including disseminated gonococcal infections, have been reported. In addition to meningitis, the risk of other infections, especially with encapsulated bacteria (eg, Streptococcus pneumoniae, H. influenzae) is increased with eculizumab treatment (because eculizumab blocks terminal complement activation). Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children should receive vaccination for prevention of S. pneumoniae, H. influenzae according to current ACIP guidelines. Use with caution when administering to patients with any systemic infection.
• Infusion reactions: Infusion reactions, including anaphylaxis or hypersensitivity, may occur; interrupt infusion for severe reaction (eg, cardiovascular instability, respiratory compromise). Continue monitoring for 1 hour after completion of infusion.
• Meningococcal infection: [US Boxed Warning]: Meningococcal (Neisseria meningitidis) infections have occurred in patients receiving eculizumab; may be fatal or life-threatening if not detected and treated promptly. Monitor closely for early signs of meningococcal infection; evaluate and treat promptly if suspected. Follow current meningococcal immunization recommendations for patients with complement deficiencies. Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Vaccinate with meningococcal vaccines at least 2 weeks prior to initiation of treatment (unless the risks of delaying eculizumab outweigh the risk of developing meningococcal infection); revaccinate according to current guidelines, considering the eculizumab duration of therapy. If eculizumab must be initiated urgently and less than 2 weeks after vaccination, provide 2 weeks of antibacterial prophylaxis. If urgent treatment is necessary in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with 2 weeks of antibacterial prophylaxis. Meningococcal infections developed in some patients despite vaccination. Prophylactic antibiotics were administered in clinical studies until at least 2 weeks after vaccination. To reduce the risk for meningococcal disease, consider antimicrobial prophylaxis with oral antibiotics (penicillin, or macrolides if penicillin-allergic) for the duration of eculizumab therapy (McNamara 2017). Discontinue eculizumab during the treatment of serious meningococcal infections. Eculizumab is associated with a ~2,000-fold increased risk of meningococcal disease (compared to the general population risk).

Concurrent drug therapy issues:

• Anticoagulation: In clinical trials, anticoagulant therapy was continued in patients who were receiving these agents (due to history of or risk for thromboembolism) prior to initiation of eculizumab. The effect of anticoagulant therapy withdrawal is unknown. Treatment with eculizumab should not alter anticoagulation management.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Discontinuation in aHUS: Monitor patients for at least 12 weeks after treatment discontinuation for signs/symptoms of thrombotic microangiopathy (TMA) complications. Signs/symptoms of TMA include angina, dyspnea, mental status changes, seizure, or thrombosis; occurrence of two or repeated measurement of any one of the following: Serum creatinine elevation (≥25% from baseline or nadir), serum LDH elevation (≥25% from baseline or nadir), thrombocytopenia (platelet decrease by ≥25% compared to baseline or peak). If TMA complications occur after stopping eculizumab, consider reinitiation of treatment, plasmapheresis, plasma exchange, fresh frozen plasma infusion, and/or appropriate organ-specific measures.
• Discontinuation in PNH: Patients with PNH who discontinue eculizumab treatment may be at increased risk for serious hemolysis; monitor closely for at least 8 weeks after treatment discontinuation.
• Immunizations: Patients should be up to date with all immunizations before initiating therapy.
• REMS program: [US Boxed Warning]: Access is restricted through a REMS program. Prescribers must be enrolled in the program; enrollment and additional information is available at 1-888-765-4747 or solirisrems.com. Counsel patients on the risk of meningococcal infection; ensure patients are vaccinated and provide educational materials.

Monitoring Parameters

CBC with differential, lactic dehydrogenase (LDH), serum creatinine, AST, urinalysis; early signs/symptoms of meningococcal infection; signs and symptoms of infusion reaction (during infusion and for 1 hour after infusion complete). Assess meningococcal vaccination status prior to initiation.

After discontinuation:

aHUS: Signs/symptoms of thrombotic microangiopathy (TMA) complications (monitor for at least 12 weeks after treatment discontinuation), including angina, dyspnea, mental status changes, seizure, or thrombosis; occurrence of two or repeated measurement of any one of the following: Serum creatinine elevation (≥25% from baseline or nadir), serum LDH elevation (≥25% from baseline or nadir), thrombocytopenia (platelet decrease by ≥25% compared to baseline or peak).

PNH: Signs and symptoms of intravascular hemolysis (monitor for at least 8 weeks after discontinuation), including anemia, fatigue, pain, dark urine, dyspnea, or thrombosis.

Pregnancy

Pregnancy Considerations

Eculizumab crosses the placenta and has been detected in cord blood in some cases (Gustavsen 2017; Kelly 2015; Miyasaka 2016; Servais 2016).

Pregnant women with PNH and their fetuses have high rates of morbidity and mortality during pregnancy and the postpartum period. Adverse maternal outcomes include bleeding, infections, miscarriages, worsening cytopenias, and thrombotic events; increased fetal death and premature delivery is also reported. Adverse maternal outcomes observed with aHUS include preeclampsia and preterm delivery; intrauterine growth restriction, low birth weight, and fetal death are also observed.

Available data, although limited, do not suggest safety concerns when eculizumab is used during pregnancy. Treatment of PNH with eculizumab has been shown to increase fetal survival and decrease maternal complications (Kelly 2015; Miyasaka 2016). Use of eculizumab for the treatment of aHUS in pregnancy has also been described (Ardissino 2013; Demir 2016; Huerta 2017; Servais 2016).

Health care providers are encouraged to enroll women exposed to eculizumab during pregnancy by contacting the disease specific registry websites (www.pnhregistry.com or www.ahusregistry.com for PNH or aHUS) or by calling 215-616-3558 (for PNH, aHUS, or gMG).

Patient Education

What is this drug used for?

• 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).
• It is used to treat myasthenia gravis.
• It is used to treat a health problem called neuromyelitis optica spectrum disorder (NMOSD).

Frequently reported side effects of this drug

• Stuffy nose
• Sore throat
• Common cold symptoms
• Flu-like symptoms
• Back pain
• Nausea
• Vomiting
• Diarrhea
• Constipation
• Abdominal pain
• Lack of appetite
• Muscle pain
• Joint pain
• Muscle spasm
• Painful extremities
• Trouble sleeping
• Hair loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Infusion reaction
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.
• Meningococcal infection like headache, fever, stiff neck, nausea, vomiting, confusion, severe muscle aches or pain, muscle cramps, or sensitivity to light
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat
• Bruising
• Not able to pass urine
• Change in amount of urine passed
• Burning or numbness feeling
• Eye irritation
• Fast heartbeat
• Vision changes
• Severe dizziness
• Passing out
• Severe headache
• Swelling of arms or legs
• Severe loss of strength and energy
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.