FRUZAQLA Capsule Ref.[107236] Active ingredients: Fruquintinib

5.1. Hypertension

FRUZAQLA can cause hypertension. Hypertension occurred in 450 of 911 (49%) patients with mCRC treated with FRUZAQLA, including Grade 3-4 events in 19%, and hypertensive crisis in three patients (0.3%). The median time to first onset of hypertension was 14 days from first dose of FRUZAQLA.

Do not initiate FRUZAQLA unless blood pressure is adequately controlled. Monitor blood pressure weekly the first month, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue FRUZAQLA based on the severity of hypertension [see Dosage and Administration (2.2)].

5.2. Hemorrhagic Events

FRUZAQLA can cause serious hemorrhagic events, which may be fatal. In 911 patients with mCRC treated with FRUZAQLA, 6% of patients experienced a gastrointestinal hemorrhage, including 13 patients (1%) with a Grade ≥3 event and 2 patients with fatal hemorrhages.

Permanently discontinue FRUZAQLA in patients with severe or life-threatening hemorrhage. Monitor the International Normalized Ratio (INR) levels in patients receiving anticoagulants [see Dosage and Administration (2.2)].

5.3. Infections

FRUZAQLA can cause an increased risk of infections, including fatal infections. In 781 patients treated with FRUZAQLA across three randomized, placebo-controlled trials, the overall incidence of infections was higher (18% vs. 12%) including for fatal infections (1% vs. 0.3%) as compared to the placebo arms (n=391).

In 911 patients with mCRC treated with FRUZAQLA, the most common infections were urinary tract infections (6.8%), upper respiratory tract infections (3.2%) and pneumonia (2.5%); fatal infections included pneumonia (0.4%), sepsis (0.2%), bacterial infection (0.1%), lower respiratory tract infection (0.1%), and septic shock (0.1%).

Withhold FRUZAQLA for Grade 3 or 4 infections, or worsening infection of any grade. Resume FRUZAQLA at the same dose when the infection has resolved.

5.4. Gastrointestinal Perforation

FRUZAQLA can cause gastrointestinal perforation. In 911 patients with mCRC treated with FRUZAQLA, 12 patients (1.3%) experienced a Grade ≥3 gastrointestinal perforation, including one fatal event.

Permanently discontinue FRUZAQLA in patients who develop gastrointestinal perforation or fistula.

5.5. Hepatotoxicity

FRUZAQLA can cause liver injury. In 911 patients with mCRC treated with FRUZAQLA, 48% experienced increased ALT or AST, including Grade ≥3 events in 5%, and fatal events in 0.2%. Median time to first onset of elevated liver enzymes was 29 days from first dose of FRUZAQLA.

Monitor liver function tests (ALT, AST, and bilirubin) before initiation and periodically throughout treatment with FRUZAQLA. Temporarily hold and then reduce or permanently discontinue FRUZAQLA depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

5.6. Proteinuria

FRUZAQLA can cause proteinuria. In 911 patients with mCRC treated with FRUZAQLA, 36% experienced proteinuria and 2.5% of patients experienced Grade ≥3 events. Median time to first onset of proteinuria was 22 days from first dose of FRUZAQLA.

Monitor for proteinuria before initiation and periodically throughout treatment with FRUZAQLA. For proteinuria ≥2 g/24 hours, withhold FRUZAQLA until improvement to ≤Grade 1 proteinuria, resume FRUZAQLA at a reduced dose. Discontinue FRUZAQLA in patients who develop nephrotic syndrome [see Dosage and Administration (2.2)].

5.7. Palmar-Plantar Erythrodysesthesia (PPE)

FRUZAQLA can cause PPE. In 911 patients with mCRC treated with FRUZAQLA, PPE occurred in 35%, including 8% with Grade 3 events. Median time to first onset of PPE was 19 days from first dose of FRUZAQLA.

Based on severity, withhold FRUZAQLA and then resume at the same or reduced dose [see Dosage and Administration (2.2)].

5.8. Posterior Reversible Encephalopathy Syndrome (PRES)

FRUZAQLA can cause PRES, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI. PRES occurred in one of 911 patients with mCRC treated with FRUZAQLA.

Perform an evaluation for PRES in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue FRUZAQLA in patients who develop PRES.

5.9. Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. In 911 patients with mCRC treated with FRUZAQLA, 1 patient experienced a Grade 2 event of wound dehiscence.

Do not administer FRUZAQLA for at least 2 weeks prior to major surgery.

Do not administer FRUZAQLA for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of FRUZAQLA after resolution of wound healing complications has not been established.

5.10. Arterial Thromboembolic Events

FRUZAQLA may increase the risk of arterial thromboembolic events. In 911 patients with mCRC treated with FRUZAQLA, 7 patients (0.8%) experienced an arterial thromboembolic event; additionally, FRUZAQLA studies excluded patients with clinically significant cardiovascular disease, uncontrolled hypertension, or with thromboembolic events within the prior 6 months. Initiation of FRUZAQLA in patients with a recent history of thromboembolic events should be carefully considered. In patients who develop arterial thromboembolism discontinue FRUZAQLA.

5.11. Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF)

FRUZAQLA 1 mg capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

FRUZAQLA 1 mg contains FD&C Yellow No. 6 (sunset yellow FCF), which may cause allergic reactions.

5.12. Embryo-Fetal Toxicity

Based on findings in animal studies and its mechanism of action, FRUZAQLA can cause fetal harm when administered to pregnant women. In an embryo-fetal developmental study in rats, embryotoxic and teratogenic effects were observed at exposures below the clinical exposure [see Use in Specific Populations (8.1)].

Advise pregnant women of the potential risk to a fetus. Advise females of childbearing potential and males with female partners of childbearing potential to use effective contraception during treatment with FRUZAQLA and for 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hypertension [see Warnings and Precautions (5.1)].
• Hemorrhagic Events [see Warnings and Precautions (5.2)].
• Infections [see Warnings and Precautions (5.3)].
• Gastrointestinal Perforation [see Warnings and Precautions (5.4)].
• Hepatotoxicity [see Warnings and Precautions (5.5)].
• Proteinuria [see Warnings and Precautions (5.6)].
• Palmar-Plantar Erythrodysesthesia (PPE) [see Warnings and Precautions (5.7)].
• Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.8)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS and below reflects exposure to FRUZAQLA as a single agent in 911 patients with mCRC who were enrolled in three randomized, placebo-controlled studies (FRESCO-2, FRESCO and 2012-013-00CH1) (N=781); three open-label studies (2009-013-00CH1, 2012-013-00CH3 and 2015-013-00US1) (N=124); and an open-label lead-in cohort of FRESCO-2 (N=6). Among the 911 patients who received FRUZAQLA, 23% were exposed for 6 months or longer and 3.5% were exposed for greater than one year. These patients received at least one dose of FRUZAQLA at the recommended dosage of 5 mg daily for the first 21 days of each 28-day cycle. The median age was 60 years (range: 23 to 82) and 34% were 65 years of age or older. The most common adverse reactions (incidence ≥20%) that occurred in pooled monotherapy studies were hypertension, PPE, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.

Metastatic Colorectal Cancer

FRESCO-2 Study

The safety of FRUZAQLA was evaluated in FRESCO-2, a randomized, double-blind, placebo-controlled study [see Clinical Studies (14.1)]. Patients received either FRUZAQLA 5 mg daily for the first 21 days of each 28-day cycle plus best supportive care (BSC) (n=456) or matching placebo plus BSC (n=230).

The median duration of therapy with FRUZAQLA was 3 months (range: 0.3 to 19.1 months).

Serious adverse reactions occurred in 38% of patients treated with FRUZAQLA. Serious adverse reactions in ≥2% of patients treated with FRUZAQLA included hemorrhage (2.2%) and gastrointestinal perforation (2.0%). Fatal adverse reaction(s) occurred in 14 (3.1%) patients who received FRUZAQLA. Fatal adverse reactions occurring in ≥2 patients include pneumonia (n=3), sepsis/septic shock (n=2), and hepatic failure/encephalopathy (n=2).

Adverse reactions leading to treatment discontinuation occurred in 20% of patients treated with FRUZAQLA. Adverse reactions leading to treatment discontinuations of FRUZAQLA in ≥1% of patients were asthenia and gastrointestinal perforation.

Dose interruptions of FRUZAQLA due to an adverse reaction occurred in 47% of patients. Adverse reactions leading to dose interruptions of FRUZAQLA in ≥2% of patients were PPE, proteinuria, asthenia, abdominal pain, hypertension, vomiting, and diarrhea.

Dose reductions of FRUZAQLA due to an adverse reaction occurred in 24% of patients. Adverse reactions leading to dose reductions of FRUZAQLA in ≥2% of patients were PPE, hypertension and asthenia.

Table 3 summarizes the adverse reactions in FRESCO-2.

Table 3. Adverse Reactions (≥10%) in Patients who Received FRUZAQLA and with a Difference Between Arms of ≥5% Compared to Placebo in FRESCO-2 (All Grades):

^* Represents a composite of multiple related terms.

Other important adverse reactions (all grades) that occurred in <10% of patients treated with FRUZAQLA included urinary tract infection (4.6%), epistaxis (3.9%), proctalgia (3.5%), pneumonia (2.4%), gastrointestinal hemorrhage (1.5%), gastrointestinal perforation (1.3%), thrombotic microangiopathy (0.2%), and posterior reversible encephalopathy syndrome (0.2%).

Table 4 provides laboratory abnormalities observed in FRESCO-2.

Table 4. Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients in FRESCO-2:

^* Graded according to NCI CTCAE version 5.0.
^† Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: FRUZAQLA (range: 409-444) and placebo (range: 195-216).

FRESCO Study

The safety of FRUZAQLA was evaluated in FRESCO, a randomized, double-blind, placebo-controlled study [see Clinical Studies (14.1)]. Patients received either FRUZAQLA 5 mg daily for the first 21 days of each 28-day cycle plus BSC (n=278) or matching placebo plus BSC (n=137).

The median duration of therapy with FRUZAQLA was 3.68 months (range: 0.3 to 22.1 months).

Serious adverse reactions occurred in 15% of patients treated with FRUZAQLA. Serious adverse reactions in ≥2% of patients included intestinal obstruction (2.9%) and hemorrhage (2.2%). Fatal adverse reaction(s) occurred in 7 (2.5%) patients who received FRUZAQLA including cerebral infarction (n=1), gastrointestinal hemorrhage (n=1), hemoptysis (n=1), bacterial infection (n=1), lung/lower respiratory infection (n=2), and multiple organ dysfunction (n=1).

Adverse reactions leading to treatment discontinuation occurred in 15% of patients who received FRUZAQLA. Adverse reactions leading to treatment discontinuations of FRUZAQLA in ≥1% were intestinal obstruction, proteinuria and hepatic function abnormalities.

Dose interruptions of FRUZAQLA due to an adverse reaction occurred in 35% of patients. Adverse reactions leading to dose interruptions of FRUZAQLA in ≥2% of patients were PPE, proteinuria, platelet count decreased, ALT increased, hypertension, and diarrhea.

Dose reductions of FRUZAQLA due to an adverse reaction occurred in 24% of patients. Adverse reactions leading to dose reduction of FRUZAQLA in ≥2% of patients were PPE, proteinuria, and hypertension.

Table 5 summarizes the adverse reactions in FRESCO.

Table 5. Adverse Reactions (≥10%) in Patients who Received FRUZAQLA and with a Difference Between Arms of ≥5% Compared to Placebo in FRESCO (All Grades):

^* Represents a composite of multiple related terms.

Other clinically important adverse reactions (all grades) that occurred in <10% of patients treated with FRUZAQLA included urinary tract infection (9%), rash (9%), upper respiratory tract infection (4.7%), proctalgia (3.6%), pneumonia (2.9%), and gastrointestinal perforation or fistula (2.2%).

Table 6 provides laboratory abnormalities observed in FRESCO.

Table 6. Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥20% of Patients in FRESCO:

^* Graded according to NCI CTCAE version 4.03.
^† Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: FRUZAQLA (range: 257-277) and placebo (range: 126-134).

7.1. Effects of Other Drugs on FRUZAQLA

Strong CYP3A Inducers

Avoid concomitant use of drugs that are strong CYP3A inducers with FRUZAQLA.

Concomitant use with a strong CYP3A inducer may decrease fruquintinib C_max and AUC [see Clinical Pharmacology (12.3)], which may reduce the efficacy of FRUZAQLA.

Moderate CYP3A Inducers

If possible, avoid concomitant use of drugs that are moderate CYP3A inducers with FRUZAQLA. If it is not possible to avoid concomitant use of a moderate CYP3A inducer and fruquintinib, continue to administer FRUZAQLA at the recommended dosage.

Concomitant use with a moderate CYP3A inducer may decrease fruquintinib C_max and AUC [see Clinical Pharmacology (12.3)], which may reduce the efficacy of FRUZAQLA.

Risk Summary

Based on findings in animal studies and its mechanism of action, FRUZAQLA can cause fetal harm when administered to a pregnant woman. In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure (see Data). There are no data on the use of FRUZAQLA in pregnant women. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In an embryo-fetal developmental study in pregnant rats, daily oral administration of fruquintinib at doses ≥0.1 mg/kg [approximately 0.2 times the recommended clinical dose of 5 mg based on body surface area (BSA)] during the period of organogenesis resulted in fetal external (edema and head and tail abnormalities), visceral, and skeletal malformations. At doses of 0.25 mg/kg (approximately 0.5 times the recommended clinical dose of 5 mg based on BSA), an increase in postimplantation loss and reduction in live fetuses was observed.

Risk Summary

There are no data regarding the presence of fruquintinib or its metabolites in human milk or its effects on a breastfed child or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with FRUZAQLA and for 2 weeks after the last dose.

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating FRUZAQLA.

Contraception

Females and Males

Females of childbearing potential and males with female partners of childbearing potential should use effective contraception during treatment and for 2 weeks after the last dose of FRUZAQLA [see Warnings and Precautions (5.11) and Nonclinical Toxicology (13.1)].

The safety and efficacy of FRUZAQLA in patients younger than 18 years of age have not been established.

In FRESCO-2, 212 (46%) patients who received FRUZAQLA were ≥65 years of age and older, of whom 43 (20%) of patients were ≥75 years. There were no observed overall differences in safety and effectiveness of FRUZAQLA in geriatric compared to younger patients.

Of the total number of FRUZAQLA-treated patients in the FRESCO study, 50 (18%) were 65 years of age and older, and one patient was ≥75 years. There were no observed overall differences in safety and effectiveness of FRUZAQLA in geriatric compared to younger patients.

No dosage adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to the ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST [see Clinical Pharmacology (12.3)].

FRUZAQLA has not been sufficiently studied in patients with moderate hepatic impairment (total bilirubin greater than 1.5 times and less than 3 times ULN and any AST). FRUZAQLA is not recommended for use in patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST).