Daunorubicin and Cytarabine (Liposomal)

Dosage Forms

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

Suspension Reconstituted, Intravenous [preservative free]:

Vyxeos: Daunorubicin 44 mg and cytarabine 100 mg (1 ea) [contains trolamine (triethanolamine)]

Pharmacology

Mechanism of Action

Daunorubicin and cytarabine (liposomal) is a combination product with a fixed 1:5 (daunorubicin:cytarabine) molar ratio; this ratio has been shown to have synergistic effects in killing leukemia cells in vitro and in animal models.

Daunorubicin (conventional) inhibits DNA and RNA synthesis by intercalation between DNA base pairs and by steric obstruction. Daunomycin intercalates at points of local uncoiling of the double helix. Although the exact mechanism is unclear, it appears that direct binding to DNA (intercalation) and inhibition of DNA repair (topoisomerase II inhibition) result in blockade of DNA and RNA synthesis and fragmentation of DNA. Cytarabine (conventional) is a pyrimidine analog and is incorporated into DNA; however, the primary action is inhibition of DNA polymerase resulting in decreased DNA synthesis and repair. The degree of cytotoxicity correlates linearly with incorporation into DNA; therefore, incorporation into the DNA is responsible for drug activity and toxicity. Cytarabine is specific for the S phase of the cell cycle (blocks progression from the G1 to the S phase).

Per animal data, liposomes are taken up intact by bone marrow cells (to a greater degree in leukemia cells versus normal bone marrow cells) and are degraded following cellular internalization, thus releasing cytarabine and daunorubicin within the cells.

Pharmacokinetics/Pharmacodynamics

Distribution

Daunorubicin: 6.6 L; Cytarabine: 7.1 L

Metabolism

Upon release from the liposomes, daunorubicin is catalyzed by aldoketo reductase and carbonyl reductase to daunorubicinol (active metabolite); cytarabine is metabolized by cytidine deaminase to Ara-U (inactive metabolite).

Excretion

Urine (9% daunorubicin; 71% cytarabine and Ara-U)

Half-Life Elimination

31.5 hours (daunorubicin); 40.4 hours (cytarabine) with >99% of drug(s) remaining encapsulated in the liposomes

Use: Labeled Indications

Acute myeloid leukemia: Treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC)

Contraindications

Serious hypersensitivity to daunorubicin, cytarabine, or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: Calculate dose based on the daunorubicin component. Prior to each dose, calculate the cumulative anthracycline exposure. Assess cardiac function, liver, and renal function prior to therapy initiation; also evaluate complete blood counts in addition to cardiac function and liver/renal function prior to each consolidation cycle. Therapy consists of 1 to 2 induction cycles followed by up to 2 consolidation cycles. Daunorubicin/cytarabine (liposomal) is associated with a moderate emetic potential; administer antiemetics prior to treatment to prevent nausea and vomiting.

Acute myeloid leukemia (newly diagnosed for therapy-related AML [t-AML] or AML with myelodysplasia-related changes [AML-MRC]): IV:

Induction (first cycle): Daunorubicin 44 mg/m² and cytarabine 100 mg/m² (liposomal) on days 1, 3, and 5

Induction (second cycle in patients who do not achieve remission with first cycle): Daunorubicin 44 mg/m² and cytarabine 100 mg/m² (liposomal) on days 1 and 3; the second induction cycle may be administered 2 to 5 weeks after the first induction cycle (if no unacceptable toxicity with previous cycle).

Consolidation: Daunorubicin 29 mg/m² and cytarabine 65 mg/m² (liposomal) on days 1 and 3; administer the first consolidation cycle 5 to 8 weeks after the start of the last induction; administer the second consolidation cycle 5 to 8 weeks after the start of the first consolidation cycle.

Missed dose: If a planned dose is missed, administer the dose as soon as possible and adjust the schedule accordingly (maintain the treatment interval).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Cardiotoxicity: Discontinue daunorubicin and cytarabine (liposomal) in patients with impaired cardiac function unless the benefits of continued treatment outweigh the toxicity risks.

Hematologic toxicity: Do not initiate a new cycle until ANC recovers to >500/mm³ and platelets recover to >50,000/mm³. Hematologic toxicity may require platelet transfusion support.

Hypersensitivity reactions:

Mild symptoms: Interrupt infusion immediately and manage symptoms as clinically appropriate. Upon symptom resolution, reinitiate infusion at 50% of the previous infusion rate; consider premedication with antihistamines and/or corticosteroids with subsequent daunorubicin and cytarabine (liposomal) doses.

Moderate symptoms: Interrupt infusion immediately and manage symptoms as clinically appropriate. Do not reinitiate infusion. Premedicate with antihistamines and/or corticosteroids with subsequent daunorubicin and cytarabine (liposomal) doses prior to initiating infusion at the same rate.

Severe or life-threatening symptoms: Interrupt infusion immediately and manage symptoms as clinically appropriate; monitor until symptom resolution. Permanently discontinue daunorubicin and cytarabine (liposomal).

Reconstitution

Allow vials to come to room temperature for 30 minutes prior to reconstitution. Reconstitute each vial with 19 mL sterile water for injection (using a sterile syringe) to a concentration of 2.2 mg/mL; swirl the vial contents for 5 minutes (using a timer) while gently inverting the vial every 30 seconds. Do not heat, vortex, or shake the vials vigorously. Allow reconstituted vials to rest for 15 minutes (product should be opaque, purple, with homogenous dispersion and essentially free of visible particulates). Gently invert each vial 5 times prior to withdrawing dose for further dilution. Transfer appropriate dose volume (dose is calculated based on the daunorubicin component) to an infusion bag containing 500 mL of NS or D5W (discard unused residual solution in the vial). Mix bag by gentle inversion; the final solution will be deep purple, translucent, with homogeneous dispersion and free from visible particulates.

Administration

Daunorubicin/cytarabine (liposomal) is associated with a moderate emetic potential; administer antiemetics prior to treatment to prevent nausea and vomiting.

IV: For IV administration only; do not administer IM or SubQ. Administer over 90 minutes (for induction and consolidation cycles) via an infusion pump through a central venous or peripherally inserted central catheter. May use an in-line membrane filter with a pore diameter ≥15 micron. Flush the line with NS or D5W after infusion. Do not mix with or administer with any other medications. If infusion-related reactions occur, premedication with antihistamines and/or corticosteroids may be necessary.

The daunorubicin (liposomal) component may be an irritant; avoid extravasation.

Storage

Store intact vials 2°C to 8°C (36°F to 46°F) in an upright position. Protect from light (retain in original container). Reconstituted solution and solutions further diluted for infusion (if not used immediately) are stable for up to 4 hours when refrigerated.

Drug Interactions

Ado-Trastuzumab Emtansine: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with ado-trastuzumab emtansine should avoid anthracycline-based therapy for up to 7 months after stopping ado-trastuzumab emtansine. Monitor closely for cardiac dysfunction in patients receiving this combination. Consider therapy modification

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

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

Bevacizumab: May enhance the cardiotoxic effect of Anthracyclines. Avoid combination

Cardiac Glycosides: May diminish the cardiotoxic effect of Anthracyclines. Anthracyclines may decrease the serum concentration of Cardiac Glycosides. The effects of liposomal formulations may be unique from those of the free drug, as liposomal formulation have unique drug disposition and toxicity profiles, and liposomes themselves may alter digoxin absorption/distribution. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

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

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

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

Cyclophosphamide: May enhance the cardiotoxic effect of Anthracyclines. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

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

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

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

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Fam-Trastuzumab Deruxtecan: May enhance the cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with fam-trastuzumab deruxtecan should avoid anthracycline-based therapy for up to 7 months after stopping fam-trastuzumab deruxtecan. Monitor closely for cardiac dysfunction in patients receiving this combination. 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

Flucytosine: Cytarabine (Conventional) may diminish the therapeutic effect of Flucytosine. Consider therapy modification

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

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

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

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

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

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

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

Taxane Derivatives: May enhance the adverse/toxic effect of Anthracyclines. Taxane Derivatives may increase the serum concentration of Anthracyclines. Taxane Derivatives may also increase the formation of toxic anthracycline metabolites in heart tissue. Consider therapy modification

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 cardiotoxic effect of Anthracyclines. Management: When possible, patients treated with trastuzumab should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab. Monitor closely for cardiac dysfunction in patients receiving anthracyclines with trastuzumab. Consider therapy modification

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: Edema (51%), cardiac arrhythmia (30%), cardiotoxicity (20%), hypotension (20%), hypertension (18%), chest pain (17%)

Central nervous system: Headache (33%), fatigue (32%), sleep disorder (25%), chills (23%), dizziness (18%), delirium (16%), anxiety (14%)

Dermatologic: Skin rash (54%), pruritus (15%)

Endocrine & metabolic: Hyponatremia (grades 3/4: 6% to 14%)

Gastrointestinal: Diarrhea (≤66%), nausea (47%), colitis (≤45%), mucositis (44%), constipation (40%), abdominal pain (33%), decreased appetite (29%), vomiting (24%), hemorrhoids (11%)

Hematologic & oncologic: Anemia (100%), neutropenia (100%; grade 4 [prolonged]: 10% to 17%), thrombocytopenia (100%; grade 3 [prolonged]: 25% to 28%), hemorrhage (70%; grades 3 to 5: 10%), febrile neutropenia (68%; grades 3 to 5: 66%), petechia (11%)

Hypersensitivity: Transfusion reaction (11%)

Infection: Bacteremia (24%), fungal infection (18%), sepsis (11%)

Local: Injection site reaction (16%; includes catheter and device site)

Neuromuscular & skeletal: Musculoskeletal pain (38%)

Ophthalmic: Visual impairment (11%)

Renal: Renal insufficiency (11%)

Respiratory: Cough (33%), dyspnea (32%), pneumonia (26%), hypoxia (18%), upper respiratory tract infection (18%), pleural effusion (16%)

Miscellaneous: Fever (17%)

1% to 10%:

Central nervous system: Hallucination (<10%)

Endocrine & metabolic: Hypokalemia (grades 3/4: 6% to 9%), hypoalbuminemia (grades 3/4: 2% to 7%), abnormal alanine aminotransferase (grades 3/4: ≤5%)

Gastrointestinal: Dyspepsia (<10%)

Hepatic: Hyperbilirubinemia (grades 3/4: 2% to 6%)

Ophthalmic: Conjunctivitis (<10%), dry eye syndrome (<10%), eye irritation (<10%), eye pain (<10%), injected sclera (<10%), ocular hyperemia (<10%), periorbital edema (<10%), swelling of eye (<10%)

Otic: Deafness (<10%)

Respiratory: Pneumonitis (<10%)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia, thrombocytopenia, and anemia occurred in all patients in a clinical study comparing daunorubicin and cytarabine (liposomal) to conventional 7 + 3 therapy; prolonged thrombocytopenia and neutropenia were also observed more frequently with the daunorubicin and cytarabine (liposomal) arm. Neutropenic fever has also been reported. Monitor blood counts frequently. Do not initiate a new cycle until ANC recovers to >500/mm³ and platelets recover to >50,000/mm³.
• Cardiotoxicity: Cardiotoxicity may occur due to the anthracycline component (daunorubicin) of the formulation. Risk factors for cardiotoxicity include prior exposure to anthracyclines, preexisting cardiac disease, previous mediastinal radiotherapy, or concomitant use of cardiotoxic medications. Other risk factors for anthracycline-induced cardiotoxicity include age 60 and older at time of treatment and 2 or more cardiovascular risk factors (smoking, hypertension, diabetes, dyslipidemia, or obesity) during or after treatment (Armenian 2017). Prior to therapy initiation, obtain an electrocardiogram (ECG), a multi-gated radionuclide angiography (MUGA) scan, or echocardiogram (ECHO) to assess cardiac function. Repeat cardiac assessment via MUGA or ECHO prior to consolidation therapy with daunorubicin and cytarabine (liposomal) and as clinically necessary. Therapy is not recommended in patients with left ventricular ejection fraction (LVEF) less than normal; discontinue in patients with abnormal cardiac function unless benefit of treatment outweighs the risks. A total cumulative dose of daunorubicin (conventional) 550 mg/m² (400 mg/m² in patients with prior mediastinal radiation) has been associated with an increased incidence of heart failure; calculate the total lifetime cumulative anthracycline dose prior to each cycle of daunorubicin and cytarabine (liposomal). Treatment is not recommended in patients whose exposure has reached the maximum cumulative threshold.
• Copper exposure: Reconstituted daunorubicin/cytarabine (liposomal) contains copper gluconate (14% elemental copper). The maximum (theoretical) total copper exposure during daunorubicin and cytarabine (liposomal) therapy is 106 mg/m². There is no clinical experience with use of this medication in patients with Wilson disease or other copper-related metabolic disorders; monitor total serum copper, serum non-ceruloplasmin bound copper, 24-hour urine copper levels and serial neuropsychological exams in these patient populations (use daunorubicin and cytarabine [liposomal] only if the benefits outweigh the risks). May require consultation with a hepatologist and nephrologist for management of acute copper toxicity; discontinue therapy if acute copper toxicity occurs.
• Extravasation: Daunorubicin (conventional) is a potent vesicant; extravasation of conventional daunorubicin has been associated with severe local tissue necrosis. The daunorubicin (liposomal) component of the formulation may be an irritant (injection site reactions have been reported). Daunorubicin/cytarabine (liposomal) is for IV administration only; do not administer IM or SubQ. Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.
• Gastrointestinal toxicity: Daunorubicin/cytarabine (liposomal) is associated with a moderate emetic potential; administer antiemetics prior to treatment to prevent nausea and vomiting. Nausea, vomiting, diarrhea/colitis, constipation, and decreased appetite have been reported with daunorubicin and cytarabine (liposomal).
• Hemorrhage: Serious hemorrhage events (associated with prolonged severe thrombocytopenia), including grade 3 and higher events, have occurred; fatal CNS hemorrhages have also been reported. In a clinical study, epistaxis was the most frequently reported hemorrhagic event. Monitor blood counts frequently; may require platelet transfusion support.
• Hypersensitivity reactions: Serious or fatal hypersensitivity reactions (including anaphylactic reactions) have been reported with daunorubicin and cytarabine; monitor closely. The infusion rate of daunorubicin and cytarabine (liposomal) may be interrupted or slowed for mild or moderate hypersensitivity reactions; manage symptoms as appropriate. If a severe or life-threatening reaction occurs, discontinue daunorubicin and cytarabine (liposomal) permanently and manage symptoms as clinically necessary. Premedication with antihistamines and or corticosteroids may be required.

Concurrent drug therapy issues:

• 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.

Special populations:

• Elderly: Bleeding events occurred more frequently in patients 65 years and older compared to younger patients.

Dosage form specific issues:

• Formulations: [US Boxed Warning]: Daunorubicin/cytarabine (liposomal) has different dosage recommendations than daunorubicin (conventional), cytarabine (conventional), daunorubicin (liposomal), and cytarabine (liposomal). Verify drug name and dose prior to preparation and administration to avoid dosing errors. The schedule and pharmacokinetics also vary among the formulations. Do not substitute other daunorubicin- or cytarabine-containing products for daunorubicin and cytarabine (liposomal).

Monitoring Parameters

Complete blood counts (prior to treatment and each consolidation cycle), liver and renal function tests (prior to treatment and each consolidation cycle), pregnancy test prior to treatment initiation (in women of reproductive potential); total serum copper, serum non-ceruloplasmin bound copper, 24-hour urine copper levels (in patients with Wilson disease or other copper-related metabolic disorders); assess cardiac function via ECG, MUGA, or ECHO prior to treatment initiation, consolidation therapy, and as clinically necessary; monitor infusion site (for extravasation), nausea/vomiting, and signs/symptoms of hemorrhage and hypersensitivity reactions

Pregnancy

Pregnancy Considerations

Based on the mechanism of action, anecdotal data of cytarabine use in pregnant women, and data from animal reproduction studies, use of daunorubicin and cytarabine (liposomal) in pregnancy may cause fetal harm.

Evaluate pregnancy status prior to use in women of reproductive potential; effective contraception should be used during therapy and for at least 6 months after the last dose. Male patients with female partners of reproductive potential should also use effective contraception during therapy and for at least 6 months after the last dose.

Also refer to individual monographs for additional information.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Mouth irritation
• Mouth sores
• Diarrhea
• Constipation
• Muscle pain
• Fatigue
• Abdominal pain
• Lack of appetite
• Trouble sleeping
• Common cold symptoms

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

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Infection
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out
• Severe injection site burning, pain, edema, or irritation
• Edema
• Chest pain
• Anxiety
• Eye pain
• Severe eye irritation
• Hearing loss
• 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.