Factor IX Complex (Human) [(Factors II, IX, X)]

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Intravenous:

Bebulin: 200-1200 units (1 ea [DSC])

Profilnine: 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea)

Profilnine SD: 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea) [contains polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

Profilnine: 500 units (1 ea); 1000 units (1 ea); 1500 units (1 ea)

Pharmacology

Mechanism of Action

Replaces deficient clotting factor including factor X; hemophilia B, or Christmas disease, is an X-linked recessively inherited disorder of blood coagulation characterized by insufficient or abnormal synthesis of the clotting protein factor IX. Factor IX is a vitamin K-dependent coagulation factor which is synthesized in the liver. Factor IX is activated by factor XIa in the intrinsic coagulation pathway. Activated factor IX (IXa), in combination with factor VII:C, activates factor X to Xa, resulting ultimately in the conversion of prothrombin to thrombin and the formation of a fibrin clot. The infusion of exogenous factor IX to replace the deficiency present in hemophilia B temporarily restores hemostasis.

Pharmacokinetics/Pharmacodynamics

Half-Life Elimination

IX component: ~19 to 25 hours

Use: Labeled Indications

Factor IX deficiency (hemophilia B [Christmas disease]): Prevention and control of bleeding in patients with factor IX deficiency (hemophilia B or Christmas disease)

Limitations of use: Not indicated for the treatment of other factor deficiencies (eg, factor II, VII, VIII, X), treatment of hemophilia A patients with inhibitors to factor VIII, or treatment of bleeding caused by low levels of liver-dependent coagulation factors.

Use: Off Label

Intracranial hemorrhage associated with warfarincyes

Data from a prospective, observational study in patients presenting with warfarin-associated intracranial hemorrhage demonstrated that the use of factor IX complex (ie, 3-factor PCC) (in combination with vitamin K with or without FFP) adequately corrected INR without increased adverse events and suggested improvement in 3-month clinical outcomes as compared to FFP Frontera 2014. In one retrospective single-center study in patients presenting with warfarin-associated intracranial hemorrhage, the use of factor IX complex (with or without FFP) was associated with serious complications and was incompletely effective in reversing warfarin anticoagulation Switzer 2012. In another retrospective study with a lower number of patients, the use of factor IX complex suggested benefit when the time to INR normalization was shortened Chong 2010. Of note, morbidity and mortality were found to remain high in this population regardless of rate of INR reversal with PCC Dowlatshahi 2012. Additional data are necessary to further define the role of factor IX complex (human) in the management of this condition.

Based on the American Heart Association/American Stroke Association (AHA/ASA) Guidelines for the Management of Spontaneous Intracerebral Hemorrhage, the use of factor IX complex (human) (ie, 3-factor PCC) may be considered for the treatment of intracranial hemorrhage associated with warfarin if it is readily available in the hospital. More recently, the Neurocritical Care Society and Society of Critical Care Medicine guidelines for the reversal of antithrombotics in intracranial hemorrhage suggests the use of 3-factor or 4-factor PCC (4-factor PCC preferred) for intracranial hemorrhage associated with warfarin when INR ≥1.4 (fresh frozen plasma may be used if PCC not available).

Life-threatening hemorrhage associated with warfarinc

Clinical experience suggests the utility of factor IX complex (in combination with vitamin K) for the emergent correction of warfarin-induced coagulopathy (with clinically significant bleeding) Liumbruno 2009. Note: Products contain low or nontherapeutic levels of factor VII component; use of fresh frozen plasma (FFP) should be considered Baker 2004, Holland 2009.

Contraindications

Profilnine: There are no contraindications listed in the manufacturer's labeling.

Bebulin: Hypersensitivity reactions to factor IX complex or any component of the formulation; known allergy to heparin; history of heparin-induced thrombocytopenia.

Dosage and Administration

Dosing: Adult

Note: Bebulin has been discontinued in the US for more than 1 year.

Note: Factor IX complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) contains low or nontherapeutic levels of factor VII component and should not be confused with Prothrombin Complex Concentrate (Human) [(Factors II, VII, IX, X), Protein C, Protein S] (Kcentra, Octaplex) which contains therapeutic levels of factor VII.

Control or prevention of bleeding in patients with factor IX deficiency (hemophilia B [Christmas disease]): Dosage is expressed in units of factor IX activity and must be individualized based on severity of factor IX deficiency, extent and location of bleeding, and clinical status of patient. Close laboratory monitoring of the factor IX level is required to determine proper dosage, particularly with severe hemorrhage and major surgery. Larger doses than those derived from the formula below may be required, especially if treatment is delayed. When multiple doses are required, administer at 24-hour intervals unless otherwise specified.

Formula for units required to raise blood level %:

Bebulin: In general, factor IX 1 unit/kg will increase the plasma factor IX level by 0.8%

Number of Factor IX units required = body weight (kg) x desired factor IX increase (as % of normal) x 1.2 units/kg

Profilnine: In general, factor IX 1 unit/kg will increase the plasma factor IX level by 1%:

Number of factor IX units required = bodyweight (kg) x desired factor IX increase (as % of normal) x 1 unit/kg

For example, to increase factor IX level to 25% of normal in a 70 kg patient: Number of factor IX units needed = 70 kg x 25 x 1 unit/kg = 1,750 units

As a general rule, the level of factor IX required for treatment of different conditions is listed below:

Hemorrhage: IV:

Minor bleeding (early hemarthrosis, minor epistaxis, gingival bleeding, mild hematuria):

Bebulin: Raise factor IX level to 20% of normal (typical initial dose: 25 to 35 units/kg); average duration of treatment is 1 day. A single dose is usually sufficient or a second dose may be given after 24 hours.

Profilnine: Raise factor IX level to 20% to 30% of normal (initial dose: 20 to 30 units/kg) every 16 to 24 hours for 1 to 2 days for minor hemorrhage or until hemorrhage stops and healing has been achieved.

Moderate bleeding (severe joint bleeding, early hematoma, major open bleeding, minor trauma, minor hemoptysis, hematemesis, melena, major hematuria):

Bebulin: Raise factor IX level to 40% of normal (typical initial dose: 50 to 65 units/kg); average duration of treatment is 2 days or until adequate wound healing.

Profilnine: Raise factor IX level to 20% to 30% of normal (initial dose: 20 to 30 units/kg) every 16 to 24 hours for 2 to 7 days for moderate hemorrhage or until hemorrhage stops and healing has been achieved.

Major bleeding (severe hematoma, major trauma, severe hemoptysis, hematemesis, melena):

Bebulin: Raise factor IX level to ≥60% of normal (typical initial dose: 75 to 90 units/kg); average duration of treatment is 2 to 3 days or until adequate wound healing.

Profilnine: Raise factor IX level to 30% to 50% of normal (initial dose: 30 to 50 units/kg) every 16 to 24 hours; following this treatment period, maintain factor IX levels at 20% of normal (maintenance dose: 20 units/kg) for 3 to 10 days or until healing has been achieved.

Surgical procedures: IV:

Dental surgery:

Bebulin: Raise factor IX level to 40% to 60% of normal on day of surgery (typical dose: 50 to 75 units/kg). One infusion, administered 1 hour prior to surgery, is generally sufficient for the extraction of one tooth; for the extraction of multiple teeth, replacement therapy may be required for up to 1 week (See dosing guidelines for Minor Surgery).

Profilnine: Raise factor IX level to 50% of normal immediately prior to procedure; maintain factor IX levels at 30% to 50% of normal (maintenance dose: 30 to 50 units/kg) every 16 to 24 hours for 7 to 10 days following surgery or until healing has been achieved.

Minor surgery:

Bebulin: Raise factor IX level to 40% to 60% of normal on day of surgery (typical initial dose: 50 to 75 units/kg). Decrease factor IX level from 40% to 60% of normal to 20% to 40% of normal during initial postoperative period (1 to 2 weeks or until adequate wound healing) [typical dose: 26 to 65 units/kg]. The preoperative dose should be given 1 hour prior to surgery. The average dosing interval may be every 12 hours initially, then every 24 hours later in the postoperative period.

Profilnine: Raise factor IX level to 30% to 50% of normal (initial dose: 30 to 50 units/kg) prior to surgery (Note: Surgery type not specified by the manufacturer); maintain factor IX levels at 30% to 50% of normal (maintenance dose: 30 to 50 units/kg) every 16 to 24 hours for 7 to 10 days following surgery or until healing is achieved.

Major surgery:

Bebulin: Raise factor IX level to ≥60% of normal on day of surgery (typical initial dose: 75 to 90 units/kg). Decrease factor IX level from ≥60% of normal to 20% to 60% of normal during initial postoperative period (1 to 2 weeks) [typical dose: 25 to 75 units/kg]; further decrease to maintain a factor IX level of 20% of normal during late postoperative period (≥3 weeks) and continuing until adequate wound healing is achieved [typical dose: 25 to 35 units/kg]. The preoperative dose should be given 1 hour prior to surgery. The average dosing interval may be every 12 hours initially, then every 24 hours later in the postoperative period.

Profilnine: Raise Factor IX level to 30% to 50% of normal (initial dose: 30 to 50 units/kg) prior to surgery (Note: Surgery type not specified by the manufacturer); maintain factor IX levels at 30% to 50% of normal (maintenance dose: 30 to 50 units/kg) every 16 to 24 hours for 7 to 10 days following surgery or until healing is achieved.

Life-threatening hemorrhage associated with warfarin (off-label use): IV: Note: Products contain low or nontherapeutic levels of factor VII component; therefore, additional fresh frozen plasma (FFP) or factor VIIa may be considered (Masotti 2011). When immediate INR reversal is required, concomitant use of 1 to 2 units of FFP should be considered to ensure acute INR reversal (Baker 2004; Holland 2009). Coadminister vitamin K (phytonadione) 5 to 10 mg by slow IV infusion (ACCP [Guyatt 2012]); vitamin K may be repeated every 12 hours if INR is persistently elevated. Factor IX complex (human) dosing has not been established in this setting; the following regimens have been used with some success.

The following 2 methods have been suggested, but are not product specific:

Adjusted-dose regimen, weight based (Liumbruno 2009):

INR <2: 20 units/kg

INR 2 to 4: 30 units/kg

INR >4: 50 units/kg

Note: If after administration, INR remains >1.5 consider repeating dose appropriate for INR.

May also determine dose based on presenting INR and estimated functional prothrombin complex (PC) expressed as percentage of normal plasma levels (see table; Masotti 2011):

Units needed to be infused = (target % of functional PC to be reached – current estimated % of functional PC) x kg of body weight

Example:

Patient (weight: 70 kg) presents with INR of 4.5 which corresponds to an estimated % functional PC of 10% (see table). Target INR of 1.4 corresponds to an estimated target % functional PC of 40%.

Units needed to be infused = (40 - 10) x 70 kg = 2,100 units

Table has been converted to the following text.

Conversion of the INR to Estimated Functional Prothrombin Complex (PC)

If INR ≥5, then estimated functional PC is 5%

If INR 4 to 4.9, then estimated functional PC is 10%

If INR 2.6 to 3.2, then estimated functional PC is 15%

If INR 2.2 to 2.5, then estimated functional PC is 20%

If INR 1.9 to 2.1, then estimated functional PC is 25%

If INR 1.7 to 1.8, then estimated functional PC is 30%

If INR 1.4 to 1.6, then estimated functional PC is 40%

If INR 1 to 1.3, then estimated functional PC is 100%

Intracranial hemorrhage associated with warfarin (off-label use): IV: Note: Factor IX complex (human) products contain low or nontherapeutic levels of factor VII component (ie, considered a 3-factor PCC). Four-factor PCC is preferred. Administer with vitamin K IV (NCS/SCCM [Frontera 2016]).

Fixed-dose regimen, weight based: INR ≥1.4: 50 units/kg; repeat INR within 15 to 60 minutes and serially every 6 to 8 hours for the next 24 to 48 hours. If INR remains ≥1.4 within the first 24 to 48 hours after initial dose, use FFP (alone) for further correction. For initial reversal, it is suggested to administer factor IX complex (PCC) alone rather than combined with FFP or recombinant factor VIIa (NCS/SCCM [Frontera 2016]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hemophilia B: Children and Adolescents: IV: Dosage is expressed in units of factor IX activity and must be individualized based on severity of factor IX deficiency, extent and location of bleeding, and clinical status of patient (WHF, 2013). When multiple doses are required, administer at 24-hour intervals unless otherwise specified.

Formula for units required to raise blood level %:

Bebulin® VH: In general, 1 unit/kg of factor IX will increase the plasma factor IX level by 0.8%

Number of Factor IX units required = body weight (kg) x desired factor IX increase (as % of normal) x 1.2 units/kg

For example, to increase factor IX level to 25% of normal in a 70 kg patient: Number of factor IX units needed = 70 kg x 25 x 1.2 unit/kg = 2100 units

Profilnine® SD: In general, 1 unit/kg of factor IX will increase the plasma factor IX level by 1%:

Number of factor IX units required = bodyweight (kg) x desired factor IX increase (as % of normal) x 1 unit/kg

For example, to increase factor IX level to 25% of normal in a 70 kg patient: Number of factor IX units needed = 70 kg x 25 x 1 unit/kg = 1750 units

As a general rule, the level of factor IX required for treatment of different conditions is listed below:

Hemorrhage:

Minor bleeding (early hemarthrosis, minor epistaxis, gingival bleeding, mild hematuria):

Bebulin® VH: Raise factor IX level to 20% of normal [typical initial dose: 25-35 units/kg]; generally a single dose is sufficient

Profilnine® SD: Mild to moderate bleeding: Raise factor IX level to 20% to 30% of normal; generally a single dose is sufficient

Moderate bleeding (severe joint bleeding, early hematoma, major open bleeding, minor trauma, minor hemoptysis, hematemesis, melena, major hematuria):

Bebulin® VH: Raise factor IX level to 40% of normal [typical initial dose: 40-55 units/kg]; average duration of treatment is 2 days or until adequate wound healing

Profilnine® SD: Mild to moderate bleeding: Raise factor IX level to 20% to 30% of normal

Major bleeding (severe hematoma, major trauma, severe hemoptysis, hematemesis, melena):

Bebulin® VH: Raise factor IX level to ≥60% of normal [typical initial dose: 60-70 units/kg]; average duration of treatment is 2-3 days or until adequate wound healing. Do not raise >60% in patients who may be predisposed to thrombosis.

Profilnine® SD: Raise factor IX level to 30% to 50% of normal; daily infusions are usually required

Surgical procedures:

Dental surgery:

Bebulin® VH: Raise factor IX level to 40% to 60% of normal on day of surgery [typical dose: 50-60 units/kg]. One infusion, administered 1 hour prior to surgery, is generally sufficient for the extraction of one tooth; for the extraction of multiple teeth, replacement therapy may be required for up to 1 week (see dosing guidelines for Minor Surgery).

Profilnine® SD: Raise factor IX level to 50% of normal immediately prior to procedure; administer additional doses if bleeding recurs

Minor surgery:

Bebulin® VH: Raise factor IX level to 40% to 60% of normal on day of surgery [typical initial dose: 50-60 units/kg]. Decrease factor IX level from 40% of normal to 20% of normal during initial postoperative period (1-2 weeks or until adequate wound healing) [typical dose: 55 units/kg decreasing to 25 units/kg]. The preoperative dose should be given 1 hour prior to surgery. The average dosing interval may be every 12 hours initially, then every 24 hours later in the postoperative period.

Profilnine® SD: Raise factor IX level to 30% to 50% of normal for at least 1 week following surgery

Major surgery:

Bebulin® VH: Raise factor IX level to ≥60% of normal on day of surgery [typical initial dose: 70-95 units/kg]; do not raise >60% in patients who may be predisposed to thrombosis. Decrease factor IX level from 60% of normal to 20% of normal during initial postoperative period (1-2 weeks) [typical dose: 70 units/kg decreasing to 35 units/kg]; further decrease to maintain a factor IX level of 20% of normal during late postoperative period (≥3 weeks) and continuing until adequate wound healing is achieved [typical dose: 35 units/kg decreasing to 25 units/kg]. The preoperative dose should be given 1 hour prior to surgery. The average dosing interval may be every 12 hours initially, then every 24 hours later in the postoperative period.

Profilnine® SD: Raise factor IX level to 30% to 50% of normal for at least 1 week following surgery

Prophylaxis, hemorrhage (long-term management): Bebulin® VH: 20-30 units/kg/dose once or twice a week may reduce frequency of spontaneous hemorrhage; dosing regimen should be individualized.

Reconstitution

Prior to reconstitution, bring diluent (sterile water for injection) and factor IX concentrate to room temperature (but not above 37°C [98.6°F]); gently rotate or agitate to dissolve, do not shake. Following reconstitution, do not refrigerate and use as soon as possible within 3 hours. Do not mix with other drugs or solvents. Vials are intended for single use (does not contain preservative); discard unused portion of the vial.

Bebulin: The reconstituted product should be a colorless to slightly yellowish and clear to slightly turbid solution.

Profilnine: A few particles may remain in solution following reconstitution; the Mix2Vial set will remove the particles and the labeled potency will not be reduced.

Administration

IV: Solution should be infused at room temperature. Rate should not exceed 2 mL/minute for Bebulin or 10 mL/minute for Profilnine. Vasomotor reactions may result from rapid administration; do not exceed the recommended infusion rates. Slowing the rate of infusion, changing the lot of medication, or administering antihistamines may relieve some adverse reactions.

Storage

Bebulin: Store undiluted vials at 2°C to 8°C (35°F to 46°F); do not freeze.

Profilnine: Storage temperature should not exceed 25°C (77°F); do not freeze.

Drug Interactions

Aminocaproic Acid: May enhance the adverse/toxic effect of Factor IX Complex (Human) [(Factors II, IX, X)]. Specifically, use of this combination may increase the risk of thrombosis. Avoid combination

Adverse Reactions

Frequency not defined.

Cardiovascular: Flushing, thrombosis (sometimes fatal)

Central nervous system: Chills, drowsiness, headache, lethargy, paresthesia

Dermatologic: Skin rash, urticaria

Gastrointestinal: Nausea, vomiting

Hematologic & oncologic: Disseminated intravascular coagulation, heparin-induced thrombocytopenia (with products containing heparin)

Hypersensitivity: Anaphylactic shock

Immunologic: Antibody development (to clotting factor)

Respiratory: Dyspnea

Miscellaneous: Fever

Warnings/Precautions

Concerns related to adverse effects:

• Antibody formation: The development of factor IX antibodies (or inhibitors) has been reported with factor IX therapy (usually occurs within the first 10 to 20 exposure days); the risk of severe hypersensitivity reactions occurring may be greater in these patients. When clinical response is suboptimal, the patient has reached a specified number of exposure days, or patient is to undergo surgical procedure, screen for inhibitors. Patients with severe hemophilia compared to those with mild or moderate hemophilia are more likely to develop inhibitors (WFH [Srivastava 2013]).
• Hypersensitivity reactions: Hypersensitivity and anaphylactic/anaphylactoid reactions have been reported with use. Delayed reactions (up to 20 days after infusion) in previously untreated patients may also occur. Due to potential for allergic reactions, the initial ~10 to 20 administrations should be performed under appropriate medical supervision. Hypersensitivity reactions may be associated with factor IX inhibitor development; patients experiencing allergic reactions should be evaluated for factor IX inhibitors. If severe hypersensitivity reactions occur, consider the use of alternative hemostatic measures (WFH [Srivastava 2013]).
• Thrombotic events: Thrombotic events (eg, deep vein thrombosis, pulmonary embolism, thrombotic strokes) as well as disseminated intravascular coagulation (DIC) have occurred. Monitor closely for signs or symptoms of intravascular coagulation or thrombosis; risk is higher in patients with congenital or acquired coagulation disorders, and with repeated dosing or high doses. Use with caution when administering to patients with liver disease, history of coronary artery disease, pre- or postoperatively, neonates, or patients at risk of thromboembolic phenomena, disseminated intravascular coagulation or patients with signs of fibrinolysis due to the potential risk of thromboembolic complications. Discontinue infusion immediately if signs or symptoms of thrombosis or embolism occur.

Disease-related concerns:

• Hepatic impairment: Use with extreme caution in patients with hepatic impairment due to the risk of thromboembolic complications.

Dosage form specific issues:

• Heparin: Some products may contain heparin. Use with caution in patients with a history of heparin-induced thrombocytopenia (use of Bebulin is contraindicated).
• Human plasma: Product of human plasma; may potentially contain infectious agents that could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer.
• Latex: Some product packaging may contain natural rubber latex.

Other warnings/precautions:

• Appropriate use: Factor IX Complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) contains low or nontherapeutic levels of factor VII component and should not be confused with Prothrombin complex concentrate (Human) [(Factors II, VII, IX, X), Protein C, Protein S] (Kcentra, Octaplex) which contains therapeutic levels of factor VII. Factor IX Complex (Human) [Factors II, IX, X] (Bebulin, Profilnine) should not be used for the treatment of factor VII deficiency. When treating warfarin-associated hemorrhage (off-label use), administration of additional fresh frozen plasma (FFP) or factor VIIa should be considered.
• Clinical response: Response to factor IX administration may vary. If bleeding is not controlled with the recommended dose, determine plasma level of factor IX and follow with a sufficient dose to achieve satisfactory clinical response. If plasma levels of factor IX fail to increase as expected or bleeding continues, suspect the presence of an inhibitor; test as appropriate.
• Immune tolerance induction: Safety and efficacy have not been established in immune tolerance induction with factor IX products. Nephrotic syndrome has occurred following immune tolerance induction in patients with hemophilia B with factor IX inhibitors receiving factor IX products.

Monitoring Parameters

Levels of factor IX; PT, PTT; INR (when used for warfarin reversal); signs and symptoms of hypersensitivity reactions, DIC, thrombosis, especially in patients with liver disease, surgical patients, and patients with known risk factors predisposing to thrombosis

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Pregnant patients with inherited coagulation disorders may have an increased bleeding risk following abortion, invasive procedures, miscarriage, and delivery; close surveillance is recommended. Clotting factors should be monitored at the first antenatal visit, once or twice during the third trimester, prior to surgical or invasive procedures, and at delivery. Although factor IX levels remain stable during pregnancy, factor IX replacement is recommended if concentrations are <0.5 IU/mL and any of the following occur: need for invasive procedures (including delivery), spontaneous miscarriage, insertion and removal of epidural catheters, or active bleeding. Hemostatic factor IX concentrations should be maintained for at least 3 to 5 days following invasive procedures or postpartum. If replacement with a factor IX concentrate is indicated to increase factor IX during pregnancy, a recombinant product is preferred. In addition, the use of factor IX concentrates that also contain factors II, VII, IX, and X (also known as PCCs) are rarely used; pure factor IX concentrations are preferred (NHF 2017; RCOG [Pavord 2017]; WFH [Srivastava 2013]).

Factor II concentrations do not increase during pregnancy. In women with severe factor II deficiency, PCCs may be administered if factor II activity is < 0.2 IU/mL with significant bleeding, during labor, or prior to cesarean delivery. Patients treated with PCCs prior to pregnancy may continue use. Factor X concentrations may increase during pregnancy; however, patients with severe factor X deficiency remain at risk for bleeding. In addition, treatment may be needed if concentrations are <0.3 IU/mL at term or prior to procedure. Hemostatic concentrations should be maintained for at least 3 days following procedures or postpartum. PCCs may be used for severe factor X deficiency in pregnancy (RCOG [Pavord 2017]).

Patient Education

What is this drug used for?

• It is used to treat hemophilia.
• It is used to treat or prevent bleeding.

Frequently reported side effects of this drug

• Flushing
• Tingling

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

• Parvovirus B19 or hepatitis A infection like chills, severe fatigue, runny nose, rash, joint pain, lack of appetite, nausea, vomiting, abdominal pain, or yellow skin
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• DVT like swelling, warmth, numbness, change in color, or pain in the extremities
• Burning or numbness feeling
• Agitation
• Nausea
• Vomiting
• Shortness of breath
• Severe dizziness
• Severe headache
• Vision changes
• Abnormal heartbeat
• Passing out
• Fast heartbeat
• Chest pain
• Coughing up blood
• Cough
• Bleeding
• 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.