C1-Esterase Inhibitor (Human)

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Complement C1 esterase inhibitor is injected into a vein through an IV. A healthcare provider will give you a Berinert in a clinic or hospital setting. You may be shown how to use Cinryze in an IV at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Complement C1 esterase inhibitor is a powder medicine that must be mixed with a liquid (diluent) before using it. If you are using Cinryze home, you will need to use two vials of Cinryze to make up a single dose. Follow all directions carefully. Be sure you understand how to properly mix and store the medicine.

Gently swirl but do not shake the mixed medicine or you may ruin it. Prepare your dose only when you are ready to give yourself an injection.

Mixed Berinert should be clear and colorless. Mixed Cinryze should be clear or slightly blue in color. Do not use the mixed medicine if it has changed colors, is cloudy, or has any particles in it. Call your doctor for a new prescription.

Cinryze is usually given every 3 or 4 days to prevent angioedema attacks. An IV infusion takes about 10 minutes to complete.

Complement C1 esterase inhibitor contains no preservative. Once you have pierced the rubber top of a vial with a needle, you must use that vial right away or throw it away.

Each single use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Store the unmixed dry powder in a refrigerator or in a dark cool place. Keep the medicine protected from light and do not allow it to freeze. Throw away any unused vial after the expiration date on the label has passed.

After mixing Berinert with the diluent, use it right away or store the mixture at room temperature and use it within 8 hours.

After mixing Cinryze with the diluent, use it right away or store the mixture at room temperature and use it within 3 hours.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include sudden headache, numbness, weakness, or problems with your speech, vision, or balance.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Since Berinert is used when needed, it does not have a daily dosing schedule. Call your doctor promptly if your symptoms do not improve after using this medicine.

Hereditary Angioedema: Prevention of Angioedema Attacks

Routine prophylaxis against angioedema attacks in adults and adolescents with hereditary angioedema (HAE).1 2 4 8 18 26 36 Designated an orphan drug by FDA for this use.3

One of several agents that may be considered for long-term prophylaxis of HAE attacks; other drugs include attenuated androgens (e.g., danazol) and antifibrinolytic agents (e.g., tranexamic acid).2 5 6 8 9 11 12 13 19 26 27 36

Consider long-term prophylaxis in patients with HAE who have frequent or severe attacks of angioedema; individualize need for prophylactic therapy based on factors such as severity of disease, frequency of attacks, patient's quality of life, availability of resources, and patient response to on-demand therapy.2 5 6 11 12 13 15 16 19 27 36

Hereditary Angioedema: Treatment of Acute Angioedema Attacks

Treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults and adolescents.21 22 26 32 37 38 39 Designated an orphan drug by FDA for this use.3

Recommended by US and international consensus guidelines as one of several options for treatment of acute HAE attacks; other drugs include ecallantide (plasma kallikrein inhibitor) and icatibant (bradykinin B2-receptor antagonist).24 26 27 29 32 36

Contraindications

• Known life-threatening hypersensitivity (e.g., anaphylaxis) to C1-esterase inhibitor (human) or any ingredient in the formulation.1 21

Warnings/Precautions

Warnings

Risk of thromboembolic events (e.g., MI, cerebrovascular accident, DVT, PE); reported in association with recommended as well as with higher than recommended (e.g., ≥100 units/kg) doses.1 17 21 28

Closely monitor patients with known risk factors for thrombosis.1 21

Potential vehicle for transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], HBV, HCV, parvovirus B19) or other infectious agents (e.g., Creutzfeldt-Jakob disease [CJD]).1 9 12 13 21 Risk substantially reduced with current donor screening practices and viral inactivating procedures; however, possibility of disease transmission still exists.1 12 15 19 21

Although cases of suspected viral transmission (including HCV) have been reported with use of Berinert outside the US, manufacturer states no causal relationship to the drug has been established since introduction of a pasteurization step in 1985.21

Weigh risks of viral infection against benefits of therapy.1 12 21 Some experts recommend that patients who receive long-term treatment with blood products be vaccinated against hepatitis A and hepatitis B.12 13 Report any suspected infections thought to be associated with C1-esterase inhibitor (human) to the manufacturer.1 21

Because of potential for airway obstruction, patients who self-administer C1-esterase inhibitor (human) for treatment of a laryngeal attack should seek immediate medical attention in an appropriate healthcare facility after the drug is administered.21

Potential for immunogenicity with use of all therapeutic proteins, including C1-esterase inhibitor (human).1 Development of noninhibitory antibodies to C1-esterase inhibitor (human) reported in clinical trials; however, clinically important effects not observed.1 38 39

Sensitivity Reactions

Risk of severe hypersensitivity reactions (e.g., hives, urticaria, chest tightness, wheezing, hypotension, anaphylaxis).1 21 If hypersensitivity occurs, discontinue drug immediately and initiate appropriate treatment.1 21 Because symptoms of hypersensitivity can resemble acute attacks of hereditary angioedema, carefully consider treatment method.1 21 Epinephrine should be available for immediate use.1 21

Specific Populations

Category C.1 21

Not known whether C1-esterase inhibitor (human) is distributed into milk.1 21 Use with caution and only if clearly needed.1 21

Safety and efficacy of Cinryze not established in neonates, infants, and children <13 years of age; use in adolescents 13–18 years of age supported by data from approval study.1 20

Safety and efficacy of Berinert not established in pediatric patients ≤12 years of age, although used successfully for the treatment of acute HAE attacks in a limited number of children as young as 6 years of age.21 25 37

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 21

Pharmacokinetics not evaluated in patients with hepatic impairment.1 21

Pharmacokinetics not evaluated in patients with renal impairment.1 21

Common Adverse Effects

Headache,1 21 22 33 nausea,1 21 22 rash,1 vomiting,1 22 dysgeusia,21 abdominal pain.21 22 33

No formal drug interaction studies to date.1 21

Absorption

Onset

Plasma concentrations of C1-esterase inhibitor increase immediately (i.e., within 1 hour) following IV administration; C4 levels subsequently rise 2–24 hours later, indicating consumption of C1-esterase inhibitor and stabilization of the complement activation system.1 5 6 8 15

Plasma Concentrations

Peak plasma concentrations attained in approximately 4 hours following a single 1000-unit dose of Cinryze.1 8

Distribution

Extent

Not known whether C1-esterase inhibitor is distributed into milk.1

Elimination

Half-life

Cinryze: Mean half-life about 56 hours (range 11–108 hours) following a single 1000-unit dose in asymptomatic patients.1 8

Berinert: Following administration of single doses (500–1500 units) in patients with mild to severe HAE, half-life approximately 18 hours in adults and 17 hours in pediatric patients 6–13 years of age.21

Difference in half-life observed between Cinryze and Berinert may be due to differences in patient populations evaluated (e.g., asymptomatic versus symptomatic).34

Special Populations

Limited data on Berinert suggest that half-life of C1-esterase inhibitor (human) may be decreased and clearance increased in pediatric patients <12 years of age compared with adults; clinical importance of such findings not known.21

• Importance of discussing potential risks and benefits of therapy with the patient prior to prescribing or administering the drug.1 21

• Importance of clinicians providing clear instructions and training on proper IV administration technique to patients self-administering C1-esterase inhibitor (human).21 Advise patients to record the lot number of the C1-esterase inhibitor (human) vial used each time they self-administer the drug.1 21

• Importance of patients not starting self-administration if an HAE attack has progressed to a point where the patient or caregiver is unable to successfully prepare or administer the drug.21

• After self-administering the drug to treat an acute laryngeal attack of HAE, importance of seeking immediate medical attention in an appropriate healthcare facility because of the potential for airway obstruction during such attacks.21

• After self-administering the drug to treat a suspected abdominal HAE attack, importance of contacting clinician to rule out the possibility of other potentially serious causes.21

• Risk of transmission of human viruses (i.e., HAV, HBV, HCV, HIV, parvovirus B19) and other infectious agents (i.e., causative agent for Creutzfeldt-Jakob disease).1 12 21 Advise patient that current donor screening and viral inactivating procedures have reduced, but not completely eliminated, the risk of disease transmission.1

• Importance of discontinuing therapy and immediately informing clinician if any signs or symptoms of hypersensitivity (e.g., rash, hives, chest tightness, wheezing, hypotension, anaphylaxis) occur.1 21

• Risk of thrombotic events; advise patients to immediately report any signs and symptoms of thrombosis (e.g., new-onset swelling and pain in the limbs or abdomen; new-onset chest pain; shortness of breath; loss of sensation or motor ability; altered consciousness, vision, or speech).21

• Advise patients to bring an adequate supply of C1-esterase inhibitor (human) while traveling and to consult a clinician prior to travel.1 21

• Advise patients to bring their drug with them when visiting a healthcare provider or facility for an acute HAE attack.21

• Importance of women informing 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 any concomitant illnesses.1 21

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