Fruquintinib – Highly Selective Oral VEGFR-1/2/3 Tyrosine Kinase Inhibitor

Fruquintinib is an oral, highly selective, and potent small-molecule inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, engineered for the systemic targeted therapy of solid tumors. The mechanism of action of fruquintinib involves blocking the autophosphorylation of kinase domains within VEGFR-1, -2, and -3 on the surface of endothelial cells, resulting in powerful suppression of the downstream VEGF signaling pathway. This disrupts endothelial cell proliferation, migration, and survival, critically halts neoangiogenesis (the formation of new blood vessels within tumor tissue), lowers intratumoral interstitial fluid pressure, and effectively stops the further metastatic dissemination and expansion of the malignant neoplasm. The core pharmacological feature of fruquintinib is its unprecedentedly high selectivity toward VEGFR kinases with minimal inhibition of other off-target kinases, which ensures a sustained therapeutic effect while minimizing risks of cross-reactive systemic toxicity.

The clinical uniqueness of fruquintinib lies in its ability to significantly extend overall survival and progression-free survival in heavily pretreated patients with metastatic colorectal cancer who have exhausted standard systemic regimens. The drug demonstrates high oral bioavailability that is not critically affected by food intake. Peak plasma exposure is achieved within a median of 2 to 4 hours post-dose. Fruquintinib is extensively bound to human plasma proteins (approximately 95%) and is primarily metabolized in the liver via the CYP3A4 isoenzyme through oxidative pathways. The mean elimination half-life is approximately 42 hours, providing stable systemic exposure. Systemic clearance of metabolites and the unchanged parent drug occurs at comparable rates via the kidneys in the urine and through the intestines in the feces.

The drug is administered orally. Prior to initiating therapy and regularly throughout its course, careful monitoring of blood pressure, hepatic function, urinary protein levels, and clinical signs of hemorrhagic complications or surgical wound healing performance is required.

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Fruquintinib

Indications

Fruquintinib is indicated as a systemic targeted monotherapy for adult patients presenting with the following malignant neoplasm:

  • Colorectal Cancer (CRC): treatment of adult patients with metastatic colorectal cancer who have been previously treated with standard fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy regimens, as well as anti-VEGF biological therapies, and, if RAS wild-type, anti-EGFR therapies, or who have medical contraindications to these agents.

Dosage and administration

The dosing regimen of fruquintinib strictly requires a cyclic alternation of treatment periods and rest phases, alongside individual assessment of treatment tolerability.

  • Standard Therapeutic Dose: the recommended starting therapeutic dose is 5 mg taken orally once daily.
  • Cyclic Schedule: the drug is administered via an intermittent regimen: 3 weeks of daily dosing (21 days), followed by a 1-week rest period (7 days off treatment). A complete treatment cycle spans 28 days. Prescribed cycles are repeated continuously until disease progression or unacceptable systemic toxicity manifests.
  • Administration Method: capsules are taken orally, at approximately the same time each day, with or without food. Capsules must be swallowed whole with a glass of water. Opening, breaking, or chewing the capsules during handling is strictly prohibited.
  • Missed Dose: if a scheduled dose is delayed by less than 12 hours, the patient must take the missed capsule immediately and resume the regular schedule. If the delay exceeds 12 hours, that dose must be skipped entirely. Taking a double dose on the following day is strictly prohibited. If vomiting occurs after taking a dose, a repeat capsule must not be administered on that day.
  • Dose Modification for Toxicity: if severe hypertension, prominent palmar-plantar erythrodysesthesia syndrome, or heavy proteinuria occurs, therapy must be temporarily withheld. Upon clinical resolution of symptoms, treatment is resumed with step-down dose reductions: first to 4 mg once daily, then to 3 mg once daily. If a patient cannot tolerate 3 mg once daily, the drug must be permanently discontinued.

The use of fruquintinib is strictly restricted by risks of systemic vascular events, bleeding liabilities, impaired tissue healing, and embryofetal harm, and is contraindicated in the following conditions:

  • Hypersensitivity: documented history of anaphylaxis, angioedema, or individual hypersensitivity to fruquintinib or any inactive formulation excipients inside the capsule shell.
  • Uncontrolled Hypertension: baseline severe elevation of blood pressure that cannot be adequately controlled via standard anti-hypertensive medicinal products, due to the high risk of hypertensive crisis and stroke.
  • Hemorrhage and Perforations: active clinically significant hemorrhage, severe bleeding diathesis, recent gastrointestinal perforations, or abdominal fistulas in the patient's medical history.
  • Surgical Interventions: perioperative windows surrounding major surgical procedures. The drug must be stopped at least 2 weeks before a planned surgery and must not be resumed for at least 2 weeks post-surgery, conditional upon complete wound healing.
  • Pregnancy and Lactation: due to its potent anti-angiogenic mechanism, the drug causes severe fetal malformations and exhibits distinct embryotoxicity. Use in pregnant women is contraindicated. Women of childbearing potential must utilize highly effective contraception methods during therapy and for 2 months after the final dose. Breastfeeding is prohibited during treatment and for 2 weeks following the last dose.
  • Pediatric Population: the safety, tolerability, and clinical efficacy profiles of fruquintinib in children and adolescents under the age of 18 have not been evaluated; use within this age cohort is contraindicated.

The side effects of fruquintinib are directly linked to its anti-angiogenic mechanism of action and class-specific effects on the vascular endothelial lining:

  • Cardiovascular System: very frequently presents as prominent blood pressure elevation (arterial hypertension) requiring combination anti-hypertensive intervention; less frequently includes myocardial ischemia and thromboembolic events.
  • Dermatological Reactions: hand-foot skin reaction (palmar-plantar erythrodysesthesia), characterized by erythema, edema, hyperkeratosis, and painful fissures on the palms and soles, alongside generalized dry skin and alopecia.
  • Urinary System: dose-dependent proteinuria (protein excretion in urine), which in severe cases can progress to nephrotic syndrome.
  • Gastrointestinal Tract: decreased appetite, taste perversion (dysgeusia), diarrhea, nausea, vomiting, stomatitis, mucosal inflammation, and epigastric pain.
  • Systemic Manifestations: pronounced dysphonia (hoarseness or loss of voice due to vocal cord paresis), profound fatigue, asthenia, hepatotoxicity (elevated ALT/AST levels), and an increased susceptibility to epistaxis.

Frequently Asked Questions

Fruquintinib is an oral targeted therapy that functions as a highly selective and potent small-molecule inhibitor of vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3). These receptors are primary drivers of angiogenesis—the physiological process through which a tumor stimulates the formation of new blood vessels to supply itself with oxygen and essential nutrients. By systematically blocking VEGFR kinases, fruquintinib cuts off the tumor's blood supply, thereby suppressing tumor growth and inhibiting further metastatic dissemination.
Fruquintinib is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC). The medication is prescribed for patients who have previously been treated with or are not candidates for available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy.
Fruquintinib is administered orally in a distinct cyclic regimen: the standard recommended dose is 5 mg once daily for 3 consecutive weeks (21 days on), followed by a mandatory 1-week rest period (7 days off). This completes a 28-day treatment cycle. The capsules should be taken at approximately the same time each day, with or without food, and must be swallowed whole with water. Adhering to this intermittent schedule is critical to mitigate drug-induced toxicities and allow normal tissues to recover.
Because VEGFR inhibition directly increases systemic vascular resistance, arterial hypertension is a highly prevalent class-effect. Patients are required to monitor and log their blood pressure daily; standard antihypertensive therapies may be initiated or adjusted by the physician. Additionally, angiogenesis inhibitors elevate the risk of bleeding events (ranging from epistaxis to gastrointestinal hemorrhage). In the event of severe, uncontrolled hypertension or persistent bleeding, fruquintinib must be withheld immediately pending emergency medical evaluation.
Patients frequently experience hand-foot syndrome (palmar-plantar erythrodysesthesia), which presents as redness, swelling, and pain on the palms and soles, requiring prophylactic emollient skin care. Crucially, VEGFR inhibitors carry a risk of gastrointestinal perforation; any acute, severe abdominal pain accompanied by fever and nausea mandates immediate emergency screening. Furthermore, fruquintinib impairs wound healing. It must be discontinued at least 2 weeks prior to any elective surgical interventions and should not be resumed for at least 2 weeks post-operatively and until adequate wound healing is confirmed.

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Fruquintinib
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