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Regorafenib

Medically reviewed by Drugs.com. Last updated on Sep 6, 2020.

Pronunciation

(re goe RAF e nib)

Index Terms

  • BAY 73-4506

Dosage Forms

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

Tablet, Oral:

Stivarga: 40 mg [contains soybean lecithin]

Brand Names: U.S.

  • Stivarga

Pharmacologic Category

  • Antineoplastic Agent, Tyrosine Kinase Inhibitor
  • Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor

Pharmacology

Regorafenib is a multikinase inhibitor; it targets kinases involved with tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment which results in inhibition of tumor growth. Specifically, it inhibits VEGF receptors 1-3, KIT, PDGFR-alpha, PDGFR-beta, RET, FGFR1 and 2, TIE2, DDR2, TrkA, Eph2A, RAF-1. BRAF, BRAFV600E, SAPK2, PTK5, and Abl.

Metabolism

Hepatic via CYP3A4 and UGT1A9, primarily to active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl)

Excretion

Feces (~71%; 47% as parent compound; 24% as metabolites); Urine (19%; 17% as glucuronides).

Time to Peak

4 hours

Half-Life Elimination

Regorafenib: 28 hours (range: 14 to 58 hours); M-2 metabolite: 25 hours (range: 14 to 32 hours); M-5 metabolite: 51 hours (range: 32 to 70 hours)

Protein Binding

99.5% to plasma proteins (active metabolites M-2 and M-5 are also highly protein bound).

Use: Labeled Indications

Colorectal cancer, metastatic: Treatment of metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and an anti-EGFR therapy (if RAS wild type).

GI stromal tumors: Treatment of locally advanced, unresectable, or metastatic GI stromal tumor in patients previously treated with imatinib and sunitinib.

Hepatocellular carcinoma: Treatment of hepatocellular carcinoma in patients previously treated with sorafenib.

Off Label Uses

Osteosarcoma, metastatic, progressive (recurrent, relapsed, or refractory)

Data from 2 small phase 2 studies support the use of regorafenib in the treatment of recurrent, relapsed, or refractory progressive metastatic osteosarcoma in patients who had received at least one prior line of systemic therapy [Davis 2019], [Duffaud 2019].

Contraindications

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

Canadian labeling: Hypersensitivity to regorafenib, any component of the formulation, or sorafenib.

Dosing: Adult

Colorectal cancer, metastatic: Oral: 160 mg once daily for the first 21 days of each 28-day cycle; continue until disease progression or unacceptable toxicity (Grothey 2013).

Reduced initial dosing strategy in metastatic colorectal cancer (off-label): Oral: Initial: 80 mg once daily, escalated weekly (if tolerated) to a goal of 160 mg once daily; administer on days 1 to 21 of a 28-day treatment cycle (Bekaii-Saab 2019).

GI stromal tumor, locally advanced, unresectable, or metastatic: Oral: 160 mg once daily for the first 21 days of each 28-day cycle; continue until disease progression or unacceptable toxicity (Demetri 2013).

Hepatocellular carcinoma: Oral: 160 mg once daily for the first 21 days of a 28-day cycle; continue until disease progression or unacceptable toxicity (Bruix 2017).

Osteosarcoma, metastatic, progressive (recurrent, relapsed, or refractory) (off-label use): Oral: 160 mg once daily on days 1 to 21 of a 28-day cycle; continue until disease progression or unacceptable toxicity (Davis 2019; Duffaud 2019).

Missed doses: Do not administer 2 doses on the same day to make up for a missed dose from the previous day.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

If dose reduction is necessary, reduce in 40 mg increments; the lowest recommended dose is 80 mg/day.

Dermatologic:

Grade 2 hand-foot skin reaction (HFSR; palmar-plantar erythrodysesthesia syndrome [PPES]) of any duration: Reduce dose to 120 mg once daily for first occurrence. If grade 2 HFSR recurs at this dose, further reduce the dose to 80 mg once daily. Interrupt therapy for grade 2 HFSR that is recurrent or fails to improve within 7 days in spite of dosage reduction.

Grade 3 HFSR: Interrupt therapy for a minimum of 7 days. Upon recovery, reduce dose to 120 mg once daily. If grade 2 to 3 toxicity recurs at this dose, further reduce dose to 80 mg once daily upon recovery. Interrupt therapy for grade 2 to 3 HFSR that is recurrent or fails to improve within 7 days in spite of dosage reduction.

Recurrent or persistent HFSR at 80 mg once daily: Discontinue treatment.

Other dermatologic toxicity: Withhold treatment, reduce dose or permanently discontinue treatment depending on the severity and persistence of the dermatologic toxicity. Symptomatic relief may be managed with supportive measures.

Hypertension: Grade 2 (symptomatic): Interrupt therapy.

Infection: Grade 3 or 4 (or worsening infection of any grade): Interrupt therapy; resume regorafenib at the same dose following infection resolution.

Other toxicity: Any grade 3 or 4 adverse reaction (other than hepatotoxicity or infection): Interrupt therapy; upon recovery, reduce dose to 120 mg once daily (except infection). If any grade 3 or 4 adverse reaction occurs (other than hepatotoxicity or infection) while on this reduced dose, may further reduce dose to 80 mg once daily upon recovery. For any grade 4 adverse reaction, only resume therapy if the benefit outweighs the risk. Permanently discontinue therapy if unable to tolerate 80 mg once daily.

Gastrointestinal perforation/fistula: Discontinue permanently.

Hemorrhage (severe or life-threatening): Discontinue permanently.

Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue.

Dosage adjustment for surgery: Temporarily withhold regorafenib at least 2 weeks prior to elective surgery; do not administer regorafenib for at least 2 weeks following major surgery and until adequate wound healing.

Administration

Oral: Administer at the same time each day. Swallow tablets whole with water after a low-fat meal (containing <600 calories and <30% fat).

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store tablets in the original bottle and protect from moisture (do not remove the desiccant); keep container tightly closed. Discard any unused tablets 7 weeks after opening the bottle.

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

BCRP/ABCG2 Substrates: Regorafenib may increase the serum concentration of BCRP/ABCG2 Substrates. Monitor therapy

Beta-Blockers: Regorafenib may enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): Regorafenib may enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Monitor therapy

Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Consider therapy modification

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Regorafenib. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Regorafenib. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Digoxin: Regorafenib may enhance the bradycardic effect of Digoxin. Monitor therapy

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Regorafenib. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Ivabradine: Regorafenib may enhance the bradycardic effect of Ivabradine. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Neomycin: May decrease serum concentrations of the active metabolite(s) of Regorafenib. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Ozanimod: BCRP/ABCG2 Inhibitors may increase serum concentrations of the active metabolite(s) of Ozanimod. Avoid combination

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Rimegepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Rimegepant. Avoid combination

Rosuvastatin: Regorafenib may increase the serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to 10 mg daily when combined with regorafenib. Monitor closely for increased rosuvastatin effects/toxicities (eg, myalgias, rhabdomyolysis) when these agents are combined. Consider therapy modification

Sacituzumab Govitecan: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Sacituzumab Govitecan. Specifically, concentrations of SN-38 may be increased. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Monitor therapy

St John's Wort: May decrease the serum concentration of Regorafenib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Ubrogepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a BCRP inhibitor. Consider therapy modification

Warfarin: May enhance the adverse/toxic effect of Regorafenib. Specifically, the risk for bleeding may be increased. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Hypertension (30% to 59%)

Central nervous system: Fatigue (≤64%), pain (55% to 59%), voice disorder (18% to 39%), headache (10% to 16%)

Dermatologic: Palmar-plantar erythrodysesthesia (45% to 67%), skin rash (26% to 30%), alopecia (7% to 24%)

Endocrine & metabolic: Hypophosphatemia (55% to 70%), hypocalcemia (17% to 59%), weight loss (13% to 32%), hypokalemia (21% to 31%), hyponatremia (30%), increased amylase (23% to 26%), hypothyroidism (6% to 18%)

Gastrointestinal: Gastrointestinal pain (60%), diarrhea (41% to 47%), decreased appetite (31% to 47%), increased serum lipase (14% to 46%), stomatitis (13% to 40%; grade ≥3: 1% to 4%), nausea (17% to 20%), vomiting (13% to 17%)

Hematologic & oncologic: Anemia (79%; grade 3: 5%; grade 4: 1%), lymphocytopenia (30% to 68%; grade 3: 8% to 16%; grade 4: 2%), thrombocytopenia (13% to 63%; grade 3: 1% to 5%; grade 4: <1%), increased INR (24% to 44%; grade 3: 4%), hemorrhage (11% to 21%; grade ≥3: 2% to 5%), neutropenia (3% to 16%; grade 3: 1% to 3%; grade 4: 1%)

Hepatic: Increased serum aspartate aminotransferase (58% to 93%), hyperbilirubinemia (33% to 78%), increased serum alanine aminotransferase (45% to 70%)

Infection: Infection (31% to 32%)

Neuromuscular & skeletal: Asthenia (≤64%), muscle spasm (10% to 14%)

Renal: Proteinuria (51% to 84%)

Miscellaneous: Fever (20% to 28%)

1% to 10%:

Dermatologic: Exfoliative dermatitis (1%)

Gastrointestinal: Mucocutaneous candidiasis (≤3%), pancreatitis (2%)

Genitourinary: Urinary tract infection (6%)

Hepatic: Hepatic failure (≤2%)

Infection: Fungal infection (≤3%)

Neuromuscular & skeletal: Tremor (1%)

Respiratory: Nasopharyngitis (4%), pneumonia (3%)

Frequency not defined: Hepatic: Hepatotoxicity

<1%, postmarketing, and/or case reports: Acute myocardial infarction, cardiac failure, erythema multiforme, gastrointestinal fistula, gastrointestinal perforation, hepatic injury, hypersensitivity reaction, hypertensive crisis, ischemic heart disease, nephrotic syndrome, reversible posterior leukoencephalopathy syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue regorafenib for hepatotoxicity as manifested by elevated liver function tests (LFTs) or hepatocellular necrosis, depending upon severity and persistence.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular events: Myocardial ischemia and infarction were observed at a higher incidence than placebo in a clinical trial. Interrupt therapy in patients who develop new or acute onset ischemia or infarction; resume only if the benefit of therapy outweighs the cardiovascular risk.

• Dermatologic toxicity: Skin reactions occurred commonly, including hand-foot skin reaction (HFSR), also known as palmar-plantar erythrodysesthesia syndrome, and severe rash requiring dose reduction. Grade 3 or 4 HFSR was observed more frequently in regorafenib-treated patients (compared to placebo), and although rare, erythema multiforme and Stevens Johnson syndrome were also observed more frequently in regorafenib-treated patients. Toxic epidermal necrolysis has also been reported (rare). Onset of HFSR typically occurs in the first cycle of treatment. Therapy interruptions, dosage reductions, and/or discontinuation may be necessary depending on the severity and persistence. Supportive treatment may be of benefit for symptomatic relief. Pooled data from several clinical trials showed a higher incidence of HFSR in Asian patients compared to Caucasians.

In addition to recommended dosage modifications, the following treatments may be used for management of HFSR (McLellan 2015): A manicure/pedicure to remove hyperkeratotic areas/calluses which may predispose to HFSR and mechanical support/correction for abnormal weight bearing prior to treatment are recommended. During treatment, patients should use alcohol-free moisturizers liberally, reduce exposure to hot water (may exacerbate hand-foot symptoms), avoid constrictive footwear and excessive skin friction, and avoid vigorous exercise/activities that may stress hands or feet. Patients should wear thick cotton gloves/socks and wear shoes with padded insoles. Grade 1 HFSR may be relieved with moisturizing creams, cotton gloves and socks (at night) and/or keratolytic creams such as urea (10% to 40%) or salicylic acid (6%) along with a topical analgesic (eg, lidocaine gel) to relieve pain. Apply topical steroid (eg, clobetasol ointment or foam) twice daily to erythematous areas of grade 2 HFSR (in addition to continuing grade 1 management); topical analgesics and then systemic analgesics (if appropriate) may be used for pain control; dose reduction may be necessary. Grade 3 HFSR should be managed by continuing grades 1 and 2 symptomatic management and interrupting treatment for at least 7 days until resolved to grade 1 or lower.

• Gastrointestinal perforation: Gastrointestinal perforation or fistula has occurred in a small number of patients treated with regorafenib; some cases were fatal. Monitor for signs/symptoms of perforation (fever, abdominal pain with constipation, and/or nausea/vomiting); permanently discontinue if perforation or fistula develop.

• Hemorrhage: The incidence of hemorrhage was increased with regorafenib. Hemorrhage of the respiratory, gastrointestinal, or genitourinary tracts was observed in trials; some cases were fatal. Permanently discontinue in patients who experience severe or life-threatening bleeding. In patients receiving concomitant warfarin, monitor INR frequently.

• Hepatotoxicity: [US Boxed Warning]: Severe and sometimes fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function at baseline and during treatment. Interrupt therapy for hepatotoxicity; dose reductions or discontinuation are necessary depending on the severity and persistence. Hepatic dysfunction, characterized by a hepatocellular injury pattern, typically occurred with the first 2 months of treatment in clinical trials. Closely monitor in patients with mild or moderate impairment for adverse events; use is not recommended in severe impairment. A higher incidence of hepatotoxicity has been observed in Asian patients (particularly Japanese), compared to Caucasians (Li 2015).

• Hypersensitivity: Hypersensitivity reactions have been observed with regorafenib.

• Hypertension: Elevated blood pressure was observed in clinical trials (onset typically in the first cycle of therapy); ensure blood pressure is adequately controlled prior to initiation. Monitor blood pressure weekly for the first 6 weeks and monthly thereafter or as clinically indicated; if hypertension develops, interrupt therapy or permanently discontinue for severe or uncontrolled hypertension. Hypertensive crisis has occurred in some patients. Patients 65 years and older had an increased incidence of grade 3 or higher hypertension (compared to younger patients).

• Infection: An increased rate of infection (including fatal events) was observed in regorafenib-treated patients in clinical trials. The most commonly reported infections were urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections, and pneumonia. Respiratory infections were the most commonly reported fatal infections. Interrupt therapy for grade 3 or 4 infections (or worsening infection of any grade).

• Reversible posterior leukoencephalopathy syndrome (RPLS): RPLS occurred very rarely in regorafenib-treated patients; evaluate promptly if symptoms (eg, seizures, severe headache, visual disturbances, confusion or altered mental function) occur. Discontinue if diagnosis is confirmed.

• Wound healing impairment: VEGF-receptor inhibitors are associated with impaired wound healing, therefore, regorafenib may affect wound healing. Withhold regorafenib treatment for ≥2 weeks prior to elective surgery; do not administer regorafenib for ≥2 weeks following major surgery and until adequate wound healing. The safety of resuming regorafenib treatment after resolution of wound healing complications has not been established.

Concurrent drug therapy issues:

• Drug-drug/drug-food 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:

• Asian patients: A higher incidence of hepatotoxicity and hand-foot skin reactions were observed in Asian patients, particularly in Japanese patients, compared to non-Asian patients (Li 2015).

• Colorectal cancer: Consider a reduced initial dose in patients with metastatic colorectal cancer. In a dose escalation study comparing an initial dose of 80 mg/day (escalated gradually to 160 mg/day on days 1 to 21 every 28 days) to the standard dose (160 mg/day on days 1 to 21 every 28 days), more patients receiving the lower initial dose were able to initiate a third treatment cycle. The lower initial dose demonstrated a decreased incidence of adverse events, with no significant difference in median overall survival, compared to the standard dose (Bekaii-Saab 2019).

Monitoring Parameters

Obtain liver function tests at baseline, every 2 weeks during the first 2 months of treatment, then monthly or more frequently if clinically necessary (weekly until improvement if liver function tests are elevated). CBC with differential and platelets and serum electrolytes (baseline and periodic). Monitor INR more frequently if receiving warfarin. Monitor blood pressure weekly for the first 6 weeks of therapy and with every subsequent cycle, or more frequently if indicated. Monitor for hand-foot skin reaction (HFSR)/palmar-plantar erythrodysesthesia syndrome (PPES); it is recommended to monitor for signs of HFSR during the first weeks of treatment, then every 1 to 2 weeks for 2 cycles, then every 4 to 6 weeks thereafter (McLellan 2015). Monitor for signs/symptoms of cardiac ischemia or infarction, bleeding, GI perforation or fistula, infection, and reversible posterior leukoencephalopathy syndrome (severe headaches, seizure, confusion, or change in vision). Monitor for impaired wound healing. Monitor adherence.

Reproductive Considerations

Women of reproductive potential and men with female partners of reproductive potential should use effective contraception during therapy and for at least 2 months following treatment.

Pregnancy Considerations

Based on animal reproduction studies and on the mechanism of action, regorafenib may cause fetal harm if administered during pregnancy.

Patient Education

What is this drug used for?

• It is used to treat cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Weight loss

• Mouth irritation

• Change in voice

• Abdominal pain

• Muscle spasm

• Hair loss

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache

• 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

• Infection

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting

• Low thyroid level like constipation; trouble handling heat or cold; memory problems; mood changes; or burning, numbness, or tingling feeling

• Severe headache

• Vision changes

• Redness or irritation of palms or soles of feet

• Severe dizziness

• Passing out

• Chest pain

• Shortness of breath

• Severe loss of strength and energy

• Abdominal swelling

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.