Xabine

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Xabine uses

• Warning: capecitabine-warfarin interaction
• Recent major changes
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Xabine reviews

WARNING: CAPECITABINE-WARFARIN INTERACTION

Capecitabine-Warfarin Interaction: Patients receiving concomitant Xabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. A clinically important Capecitabine-Warfarin drug interaction was demonstrated in a clinical pharmacology trial [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ]. Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking Xabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown clinically significant increases in prothrombin time (PT) and INR in patients who were stabilized on anticoagulants at the time Xabine was introduced. These events occurred within several days and up to several months after initiating Xabine therapy and, in a few cases, within 1 month after stopping Xabine. These events occurred in patients with and without liver metastases. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

WARNING: CAPECITABINE-WARFARIN INTERACTION

See full prescribing information for complete boxed warning.

Patients receiving concomitant Xabine and oral coumarin-derivative anticoagulants such as warfarin and phenprocoumon should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. Altered coagulation parameters and/or bleeding, including death, have been reported during concomitant use.

• Occurrence: Within several days and up to several months after initiating Xabine therapy; may also be seen within 1 month after stopping Xabine
• Predisposing factors: age>60 and diagnosis of cancer

RECENT MAJOR CHANGES

Dosage and Administration (2) 10/2014

Warnings and Precautions (5.1, 5.2, 5.5, and 5.7) 10/2014

Dosage and Administration (2.1) 12/2016

Warnings and Precautions (5.6, 5.7) 12/2016

1 INDICATIONS AND USAGE

Xabine tablets are a nucleoside metabolic inhibitor with antineoplastic activity indicated for:

• Adjuvant Colon Cancer
  • Patients with Dukes’ C colon cancer
• Metastatic Colorectal Cancer (1.1)
  • First-line as monotherapy when treatment with fluoropyrimidine therapy alone is preferred
• Metastatic Breast Cancer (1.2)
  • In combination with docetaxel after failure of prior anthracycline-containing therapy
  • As monotherapy in patients resistant to both paclitaxel and an anthracycline-containing regimen

1.1 Colorectal Cancer

• Xabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Xabine tablets were non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent Xabine tablets in the adjuvant treatment of Dukes’ C colon cancer.
• Xabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with Xabine tablets monotherapy. Use of Xabine tablets instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.

1.2 Breast Cancer

• Xabine tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
• Xabine tablets monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m² of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

2 DOSAGE AND ADMINISTRATION

• Take Xabine tablets with water within 30 min after a meal
• Monotherapy: 1250 mg/m² twice daily orally for 2 weeks followed by a one week rest period in 3-week cycles (2.2)
• Adjuvant treatment is recommended for a total of 6 months (8 cycles) (2.2)
• In combination with docetaxel, the recommended dose of Xabine tablets is 1250 mg/m² twice daily for 2 weeks followed by a 7-day rest period, combined with docetaxel at 75 mg/m² as a 1-hour IV infusion every 3 weeks (2.2)
• Xabine tablets dosage may need to be individualized to optimize patient management (2.3)
• Reduce the dose of Xabine tablets by 25% in patients with moderate renal impairment (2.4)

2.1 Important Administration Instructions

Xabine tablets should be swallowed whole with water within 30 minutes after a meal. Xabine tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures.¹ If Xabine tablets must be cut or crushed, this should be done by a professional trained in safe handling of cytotoxic drugs using appropriate equipment and safety procedures. Xabine tablets dose is calculated according to body surface area.

2.2 Standard Starting Dose

Monotherapy

The recommended dose of Xabine tablets is 1250 mg/m² administered orally twice daily (morning and evening; equivalent to 2500 mg/m² total daily dose) for 2 weeks followed by a 1-week rest period given as 3-week cycles (see Table 1).

Adjuvant treatment in patients with Dukes’ C colon cancer is recommended for a total of 6 months [ie, Xabine tablets 1250 mg/m² orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks)].

In Combination With Docetaxel (Metastatic Breast Cancer)

In combination with docetaxel, the recommended dose of Xabine tablets is 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m² as a 1-hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the Xabine tablets plus docetaxel combination. Table 1 displays the total daily dose of Xabine tablets by body surface area and the number of tablets to be taken at each dose.

2.3 Dose Management Guidelines

General

Xabine tablets dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of Xabine tablets should be modified as necessary to accommodate individual patient tolerance to treatment [see Clinical Studies (14) ]. Toxicity due to Xabine tablets administration may be managed by symptomatic treatment, dose interruptions and adjustment of Xabine tablets dose. Once the dose has been reduced, it should not be increased at a later time. Doses of Xabine tablets omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.

The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with Xabine tablets [see Drug Interactions (7.1) ].

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

Xabine tablets dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.

In Combination With Docetaxel (Metastatic Breast Cancer)

Dose modifications of Xabine tablets for toxicity should be made according to Table 2 above for Xabine tablets. At the beginning of a treatment cycle, if a treatment delay is indicated for either Xabine tablets or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.

The dose reduction schedule for docetaxel when used in combination with Xabine tablets for the treatment of metastatic breast cancer is shown in Table 3.

2.4 Adjustment of Starting Dose in Special Populations

Renal Impairment

No adjustment to the starting dose of Xabine tablets is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min [Cockroft and Gault, as shown below]). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the Xabine tablets starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m² to 950 mg/m² twice daily) is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event [see Warnings and Precautions (5.5) ]. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both Xabine tablets monotherapy and Xabine tablets in combination use with docetaxel.

Cockroft and Gault Equation:

(140 - age [yrs]) (body wt [kg])

Creatinine clearance for males = -------------

(72) (serum creatinine [mg/dL])

Creatinine clearance for females = 0.85 x male value

Geriatrics

Physicians should exercise caution in monitoring the effects of Xabine tablets, USP in the elderly. Insufficient data are available to provide a dosage recommendation.

3 DOSAGE FORMS AND STRENGTHS

Xabine tablets, USP are supplied as oblong, film-coated, biconvex, unscored tablets for oral administration. Each light peach-colored tablet contains 150 mg of Xabine, USP and each peach-colored tablet contains 500 mg of Xabine, USP.

• Tablets: 150 mg and 500 mg (3)

4 CONTRAINDICATIONS

• Severe Renal Impairment
• Hypersensitivity (4.2)

4.1 Severe Renal Impairment

Xabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min [Cockroft and Gault]) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ].

4.2 Hypersensitivity

Xabine tablets are contraindicated in patients with known hypersensitivity to Xabine or to any of its components. Xabine is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.

5 WARNINGS AND PRECAUTIONS

• Coagulopathy: May result in bleeding, death. Monitor anticoagulant response and adjust anticoagulant dose accordingly. (5.1)
• Diarrhea: May be severe. Interrupt Xabine treatment immediately until diarrhea resolves or decreases to grade 1. Recommend standard antidiarrheal treatments. (5.2)
• Cardiotoxicity: Common in patients with a prior history of coronary artery disease. (5.3)
• Increased Risk of Severe or Fatal Adverse Reactions in Patients with Lo w or Absent Dihydropyrimidine Dehydrogenase (DPD) Activity: Withhold or permanently discontinue Xabine in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No Xabine dose has been proven safe in patients with absent DPD activity. (5.4)
• Dehydration and Renal Failure: Interrupt Xabine treatment until dehydration is corrected. Potential risk of acute renal failure secondary to dehydration. Monitor and correct dehydration. (5.5)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.6, 8.1, 8.3)
• Mucocutaneous and Dermatologic Toxicity: Severe mucocutaneous reactions, Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported. Xabine should be permanently discontinued in patients who experience a severe mucocutaneous reaction during treatment. Xabine may induce hand-and-foot syndrome.. Persistent or severe hand-and-foot syndrome can lead to loss of fingerprints which could impact patient identification. Interrupt Xabine treatment until the hand-and-foot syndrome event resolves or decreases in intensity. (5.7)
• Hyperbilirubinemia: Interrupt Xabine treatment immediately until the hyperbilirubinemia resolves or decreases in intensity. (5.8)
• Hematologic: Do not treat patients with neutrophil counts <1.5 x 10⁹/L or thrombocyte counts <100 x 10⁹/L. If grade 3 to 4 neutropenia or thrombocytopenia occurs, stop therapy until condition resolves. (5.9)

5.1 Coagulopathy

Patients receiving concomitant Xabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly [see Boxed Warning and Drug Interactions (7.1)].

5.2 Diarrhea

Xabine can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received Xabine monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days. The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption, and grade 4 diarrhea as an increase of ≥10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of Xabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1 . Standard antidiarrheal treatments (eg, loperamide) are recommended.

Necrotizing enterocolitis (typhlitis) has been reported.

5.3 Cardiotoxicity

The cardiotoxicity observed with Xabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.

5.4 Dihydropyrimidine Dehydrogenase Deficiency

Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Xabine. Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by Xabine.

Withhold or permanently discontinue Xabine based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No Xabine dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

5.5 Dehydration and Renal Failure

Dehydration has been observed and may cause acute renal failure which can be fatal. Patients with pre-existing compromised renal function or who are receiving concomitant Xabine with known nephrotoxic agents are at higher risk. Patients with anorexia, asthenia, nausea, vomiting or diarrhea may rapidly become dehydrated. Monitor patients when Xabine is administered to prevent and correct dehydration at the onset. If grade 2 (or higher) dehydration occurs, Xabine treatment should be immediately interrupted and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled. Dose modifications should be applied for the precipitating adverse event as necessary .

Patients with moderate renal impairment at baseline require dose reduction [see Dosage and Administration (2.4) ]. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2 [see Dosage and Administration (2.3) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ].

5.6 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies and its mechanism of action, Xabine may cause fetal harm when given to a pregnant woman . Limited available data are not sufficient to inform use of Xabine in pregnant women. In animal reproduction studies, administration of Xabine to pregnant animals during the period of organogenesis caused embryolethality and teratogenicity in mice and embryolethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively . Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Xabine .

5.7 Mucocutaneous and Dermatologic Toxicity

Severe mucocutaneous reactions, some with fatal outcome, such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (TEN) can occur in patients treated with Xabine . Xabine should be permanently discontinued in patients who experience a severe mucocutaneous reaction possibly attributable to Xabine treatment.

Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving Xabine monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient’s activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. Persistent or severe hand-and-foot syndrome (grade 2 and above) can eventually lead to loss of fingerprints which could impact patient identification. If grade 2 or 3 hand-and-foot syndrome occurs, administration of Xabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of Xabine should be decreased [see Dosage and Administration (2.3) ].

5.8 Hyperbilirubinemia

In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of Xabine 1250 mg/m² twice daily as monotherapy for 2 weeks followed by a 1-week rest period, grade 3 hyperbilirubinemia occurred in 15.2% (n=133) of patients and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 3.9% (n=34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n=31) also had postbaseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n=46) had postbaseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n=20) and 71.7% (n=33), had liver metastases at baseline. In addition, 57.5% (n=96) and 35.3% (n=59) of the 167 patients had elevations (grades 1 to 4) at both prebaseline and postbaseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n=13) and 3% (n=5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.

In the 596 patients treated with Xabine as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of Xabine monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with Xabine. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.

In 251 patients with metastatic breast cancer who received a combination of Xabine and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n=17) and grade 4 (>3 x ULN) hyperbilirubinemia occurred in 2% (n=5).

If drug-related grade 3 to 4 elevations in bilirubin occur, administration of Xabine should be immediately interrupted until the hyperbilirubinemia decreases to ≤3 X ULN [see recommended dose modifications under Dosage and Administration (2.3) ].

5.9 Hematologic

In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m² administered twice daily as monotherapy for 2 weeks followed by a 1-week rest period, 3.2%, 1.7%, and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of Xabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia, and 9.6% had grade 3 or 4 anemia.

Patients with baseline neutrophil counts of <1.5 x 10⁹/L and/or thrombocyte counts of <100 x 10⁹/L should not be treated with Xabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with Xabine should be interrupted.

5.10 Geriatric Patients

Patients ≥80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received Xabine monotherapy, 62% of the 21 patients ≥80 years of age treated with Xabine experienced a treatment-related grade 3 or 4 adverse event: diarrhea in 6, nausea in 3 (14.3%), hand-and-foot syndrome in 3 (14.3%), and vomiting in 2 (9.5%) patients. Among the 10 patients 70 years of age and greater (no patients were >80 years of age) treated with Xabine in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis, and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.

Among the 67 patients ≥60 years of age receiving Xabine in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the <60 years of age patient group.

In 995 patients receiving Xabine as adjuvant therapy for Dukes’ C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥65 years of age treated with Xabine experienced a treatment-related grade 3 or 4 adverse event: hand-and-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in 6 (1.5%), and nausea in 5 (1.3%) patients. In patients ≥65 years of age (all randomized population; Xabine 188 patients, 5-FU/LV 208 patients) treated for Dukes’ C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for Xabine compared to 5-FU/LV were 1.01 (95% C.I. 0.80 to 1.27) and 1.04 (95% C.I. 0.79 to 1.37), respectively.

5.11 Hepatic Insufficiency

Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when Xabine is administered. The effect of severe hepatic dysfunction on the disposition of Xabine is not known [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

5.12 Combination With Other Drugs

Use of Xabine in combination with irinotecan has not been adequately studied.

6 ADVERSE REACTIONS

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.

Most common adverse reactions were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Adjuvant Colon Cancer

Table 4 shows the adverse reactions occurring in ≥5% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m² twice a day of Xabine administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5-FU on days 1 to 5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) Xabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to Xabine and 10 (1%) randomized to 5-FU/LV.

Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥1% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment.

6.2 Metastatic Colorectal Cancer

Monotherapy

Table 6 shows the adverse reactions occurring in ≥5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m² twice a day of Xabine administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen. In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) Xabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to Xabine and 32 (5.4%) randomized to 5-FU/LV.

6.3 Breast Cancer

In Combination with Docetaxel

The following data are shown for the combination study with Xabine and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the Xabine and docetaxel combination arm the treatment was Xabine administered orally 1250 mg/m² twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m² on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m² on the first day of each 3-week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.

Monotherapy

The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m² administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.

6.4 Clinically Relevant Adverse Events in <5% of Patients

Clinically relevant adverse events reported in <5% of patients treated with Xabine either as monotherapy or in combination with docetaxel that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses.

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%)

Skin & Subcutan.: nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%)

General: chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation

Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance

Metabolism: increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia

Eye: conjunctivitis

Respiratory: cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea

Cardiac: tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion

Infections: laryngitis (1%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%)

Musculoskeletal: myalgia, bone pain (0.1%), arthritis (0.1%), muscle weakness

Blood & Lymphatic: leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1%), pancytopenia (0.1%)

Vascular: hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%)

Psychiatric: depression, confusion (0.1%)

Renal: renal impairment (0.6%)

Ear: vertigo

Hepatobiliary: hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function tests

Immune System: drug hypersensitivity (0.1%)

Postmarketing: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome , cutaneous lupus erythematosus, corneal disorders including keratitis, toxic leukoencephalopathy, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) , persistent or severe hand-and-foot syndrome can eventually lead to loss of fingerprints

Xabine In Combination With Docetaxel (Metastatic Breast Cancer)

Gastrointestinal: ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%)

Neurological: ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%)

Cardiac: supraventricular tachycardia (0.4%)

Infection: neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%)

Blood & Lymphatic: agranulocytosis (0.4%), prothrombin decreased (0.4%)

Vascular: hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%)

Renal: renal failure (0.4%)

Hepatobiliary: jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%)

Immune System: hypersensitivity (1.2%)

7 DRUG INTERACTIONS

• Anticoagulants: Monitor anticoagulant response frequently in order to adjust the anticoagulant dose as needed. (5.1, 7.1)
• Phenytoin: Monitor phenytoin levels in patients taking Xabine concomitantly with phenytoin. The phenytoin dose may need to be reduced. (7.1)
• Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. (7.1)
• CYP2C9 substrates: Care should be exercised when Xabine is co-administered with CYP2C9 substrates. (7.1)
• Food reduced both the rate and extent of absorption of Xabine. (2, 7.1, 12.3)

7.1 Drug-Drug Interactions

Anticoagulants

Altered coagulation parameters and/or bleeding have been reported in patients taking Xabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon [see Boxed Warning ]. These events occurred within several days and up to several months after initiating Xabine therapy and, in a few cases, within 1 month after stopping Xabine. These events occurred in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin [see Clinical Pharmacology (12.3) ]. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by Xabine and/or its metabolites.

Phenytoin

The level of phenytoin should be carefully monitored in patients taking Xabine and phenytoin dose may need to be reduced [see Dosage and Administration (2.3) ]. Postmarketing reports indicate that some patients receiving Xabine and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by Xabine and/or its metabolites.

Leucovorin

The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.

CYP2C9 substrates

Other than warfarin, no formal drug-drug interaction studies between Xabine and other CYP2C9 substrates have been conducted. Care should be exercised when Xabine is co-administered with CYP2C9 substrates.

7.2 Drug-Food Interaction

Food was shown to reduce both the rate and extent of absorption of Xabine [see Clinical Pharmacology (12.3) ]. In all clinical trials, patients were instructed to administer Xabine within 30 minutes after a meal. It is recommended that Xabine be administered with food [see Dosage and Administration (2) ].

8 USE IN SPECIFIC POPULATIONS

• Lactation: Advise women not to breastfeed.
• Females and Males of Reproductive Potential: Verify pregnancy status of females prior to initiation of Xabine. Advise males with female partners of reproductive potential to use effective contraception. (8.3)
• Geriatric: Greater incidence of adverse reactions. Monitoring required. (8.5)
• Hepatic Impairment: Monitoring is recommended in patients with mild to moderate hepatic impairment. (8.6)
• Renal Impairment: Reduce Xabine starting dose in patients with moderate renal impairment (2.3, 8.7, 12.3)

8.1 Pregnancy

Risk Summary

Based on findings in animal reproduction studies and its mechanism of action, Xabine can cause fetal harm when administered to a pregnant woman . Limited available human data are not sufficient to inform the drug-associated risk during pregnancy. In animal reproduction studies, administration of Xabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose respectively . Apprise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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

Oral administration of Xabine to pregnant mice during the period of organogenesis at a dose of 198 mg/kg/day caused malformations and embryo lethality. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values that were approximately 0.2 times the AUC values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. Oral administration of Xabine to pregnant monkeys during the period of organogenesis at a dose of 90 mg/kg/day, caused fetal lethality. This dose produced 5’-DFUR AUC values that were approximately 0.6 times the AUC values in patients administered the recommended daily dose.

8.2 Lactation

Risk Summary

There is no information regarding the presence of Xabine in human milk, or on its effects on milk production or the breast-fed infant. Xabine metabolites were present in the milk of lactating mice . Because of the potential for serious adverse reactions from Xabine exposure in breast-fed infants, advise women not to breastfeed during treatment with Xabine and for 2 weeks after the final dose.

Data

Lactating mice given a single oral dose of Xabine excreted significant amounts of Xabine metabolites into the milk.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating Xabine.

Contraception

Females

Xabine can cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the final dose of Xabine.

Males

Based on genetic toxicity findings, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months following the last dose of Xabine .

Infertility

Based on animal studies, Xabine may impair fertility in females and males of reproductive potential .

8.4 Pediatric Use

The safety and effectiveness of Xabine in pediatric patients have not been established.

Additional information from the two clinical studies in which efficacy was not demonstrated in certain pediatric patients is approved for Hoffmann La Roches' Xeloda (capecitabine) tablets. However, due to Hoffman La Roche's marketing exclusivity rights, this product is not labeled with that information.

8.5 Geriatric Use

Physicians should pay particular attention to monitoring the adverse effects of Xabine in the elderly [see Warnings and Precautions ].

8.6 Hepatic Insufficiency

Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with Xabine. The effect of severe hepatic dysfunction on Xabine is not known [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3) ].

8.7 Renal Insufficiency

Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for Xabine, 5-DFUR, and FBAL than in those with normal renal function [see Contraindications (4.1) , Warnings and Precautions (5.5) , Dosage and Administration (2.4) , and Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression. Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for Xabine overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5’-DFUR, a low-molecular-weight metabolite of the parent compound.

Single doses of Xabine were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m² basis).

11 DESCRIPTION

Xabine, USP is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-fluorouracil.

The chemical name for Xabine, USP is 5’-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Xabine, USP has the following structural formula:

Xabine, USP is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20ºC.

Xabine tablets, USP are supplied as oblong, film-coated, biconvex unscored tablets for oral administration. Each light peach-colored tablet contains 150 mg Xabine, USP and each peach-colored tablet contains 500 mg Xabine, USP. The inactive ingredients in Xabine tablets, USP include: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and purified water. The peach or light peach film-coating contains iron oxide red, iron oxide yellow, macrogol, polyvinyl alcohol, talc and titanium dioxide.

8649c6ce-figure-01

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Enzymes convert Xabine to 5-fluorouracil in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2’-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N^5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2’-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.

12.3 Pharmacokinetics

Absorption

Following oral administration of 1255 mg/m² BID to cancer patients, Xabine reached peak blood levels in about 1.5 hours (T_max) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of Xabine with mean C_max and AUC_0-∞ decreased by 60% and 35%, respectively. The C_max and AUC_0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed T_max of both parent and 5-FU by 1.5 hours [see Warnings and Precautions (5) , Dosage and Administration (2) , and Drug-Food Interaction (7.2) ].

The pharmacokinetics of Xabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m²/day. Over this range, the pharmacokinetics of Xabine and its metabolite, 5’-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5’-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the C_max and AUC of 5-FU was greater than 85%.

Distribution

Plasma protein binding of Xabine and its metabolites is less than 60% and is not concentration-dependent. Xabine was primarily bound to human albumin (approximately 35%). Xabine has a low potential for pharmacokinetic interactions related to plasma protein binding.

Bioactivation and Metabolism

Xabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5’-deoxy-5-fluorocytidine (5’-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5’-DFCR to 5’-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5’-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of Xabine 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.

Metabolic Pathway of Xabine to 5-FU

The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of Xabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH₂). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine.

In vitro enzymatic studies with human liver microsomes indicated that Xabine and its metabolites (5’DFUR, 5’-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.

Excretion

Xabine and its metabolites are predominantly excreted in urine; 95.5% of administered Xabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent Xabine and 5-FU was about 0.75 hour.

Effect of Age, Gender, and Race on the Pharmacokinetics of Xabine

A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered Xabine at 1250 mg/m² twice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5’-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5’-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL [see Warnings and Precautions (5.11) and Dosage and Administration (2.4) ].

Following oral administration of 825 mg/m² Xabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower C_max and 24% lower AUC for Xabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower C_max and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5’-DFCR, 5’-DFUR, and 5-FU).

Effect of Hepatic Insufficiency

Xabine has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/m² dose of Xabine. Both AUC_0-∞ and C_max of Xabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC_0-∞ and C_max of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when Xabine is administered. The effect of severe hepatic dysfunction on Xabine is not known [see Warnings and Precautions (5.11) and Use in Special Populations (8.6) ].

Effect of Renal Insufficiency

Following oral administration of 1250 mg/m² Xabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance >80 mL/min). Systemic exposure to 5’-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to Xabine was about 25% greater in both moderately and severely renal impaired patients [see Dosage and Administration (2.4) , Contraindications (4.1) , Warnings and Precautions (5.5) , and Use in Special Populations (8.7) ].

Effect of Xabine on the Pharmacokinetics of Warfarin

In four patients with cancer, chronic administration of Xabine (1250 mg/m² bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91% [see Boxed Warning and Drug Interactions (7.1) ].

Effect of Antacids on the Pharmacokinetics of Xabine

When Maalox ^® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after Xabine (1250 mg/m², n=12 cancer patients), AUC and C_max increased by 16% and 35%, respectively, for Xabine and by 18% and 22%, respectively, for 5’-DFCR. No effect was observed on the other three major metabolites (5’-DFUR, 5-FU, FBAL) of Xabine.

Effect of Xabine on the Pharmacokinetics of Docetaxel and Vice Versa

A Phase 1 study evaluated the effect of Xabine on the pharmacokinetics of docetaxel (Taxotere^®) and the effect of docetaxel on the pharmacokinetics of Xabine was conducted in 26 patients with solid tumors. Xabine was found to have no effect on the pharmacokinetics of docetaxel (C_max and AUC) and docetaxel has no effect on the pharmacokinetics of Xabine and the 5-FU precursor 5’-DFUR.

8649c6ce-figure-02

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Adequate studies investigating the carcinogenic potential of Xabine have not been conducted. Xabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Xabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.

In studies of fertility and general reproductive performance in female mice, oral Xabine doses of 760 mg/kg/day (about 2300 mg/m²/day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose.

14 CLINICAL STUDIES

14.1 Adjuvant Colon Cancer

A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes’ C colon cancer provided data concerning the use of Xabine for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving Xabine to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with Xabine 1250 mg/m² orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m² and 20 mg/m² IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes’ stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5x10⁹/L, platelets ≥ 100x10⁹/L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.

The baseline demographics for Xabine and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.

All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m² orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline [see Dosage and Administration (2.4) ]. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for Xabine included dose reductions, cycle delays and treatment interruptions (see Table 11).

The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for Xabine compared to 5-FU/LV was 0.88 (95% C.I. 0.77 to 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, Xabine was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for Xabine compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 to 1.01). The 5-year overall survival rates were 71.4% for Xabine and 68.4% for 5-FU/LV (see Figure 2).

Figure 1 Kaplan-Meier Estimates of Disease-Free Survival (All Randomized Population) ^a

^a Xabine has been demonstrated to be non-inferior to 5-FU/LV.

Figure 2 Kaplan-Meier Estimates of Overall Survival (All Randomized Population)

8649c6ce-figure-03 8649c6ce-figure-04

14.2 Metastatic Colorectal Cancer

General

The recommended dose of Xabine was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with Xabine (1331 mg/m²/day in two divided doses, n=39), intermittent therapy with Xabine (2510 mg/m²/day in two divided doses, n=34), and intermittent therapy with Xabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m²/day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to Xabine; however, toxicity was increased. Xabine, 1250 mg/m² twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.

Monotherapy

Data from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of Xabine in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with Xabine at a dose of 1250 mg/m² twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5-FU, on days 1 to 5, every 28 days).

In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non-inferiority analysis.

The baseline demographics for Xabine and 5-FU/LV patients are shown in Table 13.

The efficacy endpoints for the two phase 3 trials are shown in Table 14 and Table 15.

Figure 3 Kaplan-Meier Curve for Overall Survival of Pooled Data (Studies 1 and 2)

Xabine was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of Xabine and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that Xabine has a clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by Xabine. The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and Xabine, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1. The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs Xabine difference. These results do not exclude the possibility of true equivalence of Xabine to 5-FU/LV (see Table 14 , Table 15 , and Figure 3).

8649c6ce-figure-05

14.3 Breast Cancer

Xabine has been evaluated in clinical trials in combination with docetaxel (Taxotere ^® ) and as monotherapy.

In Combination With Docetaxel

The dose of Xabine used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of Xabine (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m² administered in 3week cycles of docetaxel in combination with 1250 mg/m² twice daily for 14 days of Xabine administered in 3-week cycles. The approved dose of 100 mg/m² of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.

Xabine in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive Xabine 1250 mg/m² twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m² as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m² as a 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.

Xabine in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.

Figure 4 Kaplan-Meier Estimates for Time to Disease Progression Xabine and Docetaxel vs Docetaxel

Figure 5 Kaplan-Meier Estimates of Survival Xabine and Docetaxel vs Docetaxel

Monotherapy

The antitumor activity of Xabine as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. Xabine was administered at a dose of 1255 mg/m² twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen.

Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.

For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18). The median time to progression was 90 days and the median survival was 306 days.

8649c6ce-figure-06 8649c6ce-figure-07

15 REFERENCES

• ”OSHA Hazardous Drugs.” OSHA.
  

  http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 HOW SUPPLIED/STORAGE AND HANDLING

Xabine tablets, USP, 150 mg, are supplied as light peach, oblong, film-coated, biconvex, unscored tablets, debossed with ‘AN’ on one side and ‘843’ on the other side.

They are available as follows:

Bottles of 60: NDC 65162-843-06

Xabine tablets, USP, 500 mg, are supplied as peach, oblong, film-coated, biconvex, unscored tablets, debossed with ‘AN’ on one side and ‘844’ on the other side

They are available as follows:

Bottles of 60: NDC 65162-844-06

Bottles of 120: NDC 65162-844-16

Bottles of 500: NDC 65162-844-50

Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). KEEP TIGHTLY CLOSED.

Xabine tablets, USP are a cytotoxic drug. Follow applicable special handling and disposal procedures.¹ Any unused product should be disposed of in accordance with local requirements, or drug take back programs.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients and patients’ caregivers should be informed of the expected adverse effects of Xabine, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary [see Dosage and Administration (2.3) ]. As described below, patients taking Xabine should be informed of the need to interrupt treatment and to call their physician immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with Xabine treatment. See FDA-approved patient labeling (Patient Information).

Dihydropyrimidine Dehydrogenase Deficiency

Patients should be advised to notify their healthcare provider if they have a known DPD deficiency. Advise patients if they have complete or near complete absence of DPD activity they are at an increased risk of acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by Xabine (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity) .

Diarrhea

Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater or experiencing severe bloody diarrhea with severe abdominal pain and fever should be instructed to stop taking Xabine and call their physician immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.

Dehydration

Patients experiencing grade 2 or higher dehydration should be instructed to stop taking Xabine immediately and the dehydration corrected. Treatment should not be restarted until the patient is rehydrated and any precipitating causes have been corrected or controlled.

Nausea

Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking Xabine immediately. Initiation of symptomatic treatment is recommended.

Vomiting

Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking Xabine immediately. Initiation of symptomatic treatment is recommended.

Hand-and-Foot Syndrome

Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients’ activities of daily living) or greater should be instructed to stop taking Xabine immediately. Initiation of symptomatic treatment is recommended. Hand-and-foot syndrome can lead to loss of fingerprints which could impact your identification.

Stomatitis

Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking Xabine immediately and to call their physician. Initiation of symptomatic treatment is recommended.

Fever and Neutropenia

Patients who develop a fever of 100.5°F or greater or other evidence of potential infection should be instructed to call their physician immediately.

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with Xabine and for 6 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1 and 8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Xabine and for 3 months after the last dose .

Lactation

Advise females not to breastfeed during treatment with Xabine and for 2 weeks after the last dose .

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 12-2016-00

Patient Information

Xabine (KAP-e-SYE-ta-been) Tablets USP, Film-Coated

What is the most important information I should know about Xabine tablets?

Xabine tablets can cause serious side effects, including:

• Xabine tablets can interact with blood thinner medicines, such as warfarin (COUMADIN^®). Taking Xabine tablets with these medicines can cause changes in how fast your blood clots, and can cause bleeding that can lead to death. This can happen as soon as a few days after you start taking Xabine tablets, or later during treatment, and possibly even within 1 month after you stop taking Xabine tablets. Your risk may be higher because you have cancer, and if you are over 60 years of age.
  • Before taking Xabine tablets, tell your doctor if you are taking warfarin (COUMADIN) or another blood thinner medicine.
  • If you take warfarin (COUMADIN) or another blood thinner that is like warfarin (COUMADIN) during treatment with Xabine tablets, your doctor should do blood tests often, to check how fast your blood clots during and after you stop treatment with Xabine tablets. Your doctor may change your dose of the blood thinner medicine if needed.

See “What are the possible side effects of Xabine tablets?” for more information about side effects.

What are Xabine tablets?

Xabine tablets are a prescription medicine used to treat people with:

• cancer of the colon that has spread to lymph nodes in the area close to the colon (Dukes’ C stage), after they have surgery.
• cancer of the colon or rectum (colorectal) that has spread to other parts of the body (metastatic ).
• breast cancer that has spread to other parts of the body (metastatic) together with another medicine called docetaxel after treatment with certain other anti-cancer medicines have not worked.
• breast cancer that has spread to other parts of the body and has not improved after treatment with paclitaxel and certain other anti-cancer medicines, or who cannot receive any more treatment with certain anti-cancer medicines.

It is not known if Xabine tablets are safe and effective in children.

Who should not take Xabine tablets?

Do not take Xabine tablets if you:

• have severe kidney problems.
• are allergic to Xabine, 5-fluorouracil or to any of the ingredients in Xabine tablets. See the end of this leaflet for a complete list of ingredients in Xabine tablets.

Talk to your doctor before taking Xabine tablets if you are not sure if you have any of the conditions listed above.

What should I tell my doctor before taking Xabine tablets?

See “What is the most important information I should know about Xabine tablets?”

Before you take Xabine tablets, tell your doctor if you:

• have had heart problems.
• have kidney or liver problems.
• have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)
• have any other medical conditions.
• are pregnant or plan to become pregnant. Xabine tablets may harm your unborn baby. You should not become pregnant during treatment with Xabine tablets. Talk to your doctor about birth control choices that may be right for you during treatment with Xabine tablets.
• are breastfeeding or plan to breastfeed. It is not known if Xabine passes into your breast milk. Do not breastfeed during treatment with Xabine tablets.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Xabine tablets may affect the way other medicines work, and other medicines may affect the way Xabine tablets work.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Xabine tablets?

• Take Xabine tablets exactly as your doctor tells you to take it.
• Your doctor will tell you how much Xabine tablets to take and when to take it.
• Take Xabine tablets 2 times a day, 1 time in the morning and 1 time in the evening.
• Take Xabine tablets within 30 minutes after finishing a meal. Swallow Xabine tablets whole with water. Do not crush or cut Xabine tablets.
• Ask your healthcare provider or pharmacist how to safely throw away any unused Xabine tablets.
• If you have side effects with Xabine tablets, if needed your doctor may decide to:
  • change your dose of Xabine tablets
  • treat you with Xabine tablets less often
  • tell you to stop taking Xabine tablets until certain side effects get better or go away
  • stop your treatment with Xabine tablets if you have certain side effects and they are severe
• If you take too much Xabine tablets, call your doctor or go to the nearest emergency room right away.

What are the possible side effects of Xabine tablets?

Xabine tablets may cause serious side effects including:

See “What is the most important information I should know about Xabine tablets?”

• diarrhea. Diarrhea is common with Xabine tablets and can sometimes be severe. Stop taking Xabine tablets and call your doctor right away if the number of bowel movements you have in a day increases by 4 or more than is usual for you. Ask your doctor about what medicines you can take to treat your diarrhea. If you have severe bloody diarrhea with severe abdominal pain and fever, call your doctor or go to the nearest emergency room right away.
• heart problems. Xabine tablets can cause heart problems including: heart attack and decreased blood flow to the heart, chest pain, irregular heartbeats, changes in the electrical activity of your heart seen on an electrocardiogram (ECG), problems with your heart muscle, heart failure, and sudden death. Stop taking Xabine tablets and call your doctor right away if you get any of the following symptoms:
• unexplained tiredness
• loss of too much body fluid (dehydration) and kidney failure.
  

  Dehydration can happen with Xabine tablets and may cause sudden kidney failure that can lead to death. You are at higher risk if you have kidney problems before taking Xabine tablets and also take other medicines that can cause kidney problems.

Nausea, and vomiting are common with Xabine tablets. If you lose your appetite, feel weak, and have nausea, vomiting, or diarrhea, you can quickly become dehydrated.

Stop taking Xabine tablets and call your doctor right away if you:

• vomit 2 or more times in a day.
• are only able to eat or drink a little now and then, or not at all due to nausea.
• have diarrhea. See “diarrhea” above.
• serious skin and mouth reactions.
• Xabine tablets can cause serious skin reactions that may lead to death. Tell your doctor right away if you develop a skin rash, blisters and peeling of your skin. Your doctor may tell you to stop taking Xabine tablets if you have a serious skin reaction. Do not take Xabine tablets again if this happens.
• Xabine tablets can also cause “hand and foot syndrome.” Hand and foot syndrome is common with Xabine tablets and can cause you to have numbness and changes in sensation in your hands and feet, or cause redness, pain, swelling of your hands and feet. Stop taking Xabine tablets and call your doctor right away if you have any of these symptoms and you are not able to do your usual activities. Hand and foot syndrome can lead to loss of fingerprints which could impact your identification.
• you may get sores in your mouth or on your tongue when taking Xabine tablets. Stop taking Xabine tablets and call your doctor if you get painful redness, swelling, or ulcers in your mouth and tongue, or if you are having problems eating. Tell your doctor if you have any side effect that bothers you or that does not go away.
• increased level of bilirubin in your blood and liver problems. Increased bilirubin in your blood is common with Xabine tablets. Your doctor will check you for these problems during treatment with Xabine tablets.
• decreased white blood cells, platelets, and red blood cell counts. Your doctor will do blood tests during treatment with Xabine tablets to check your blood cell counts.

If your white blood cell count is very low, you are at increased risk for infection. Call your doctor right away if you develop a fever of 100.5°F or greater or have other signs and symptoms of infection.

People 80 years of age or older may be more likely to develop severe or serious side effects with Xabine tablets.

The most common side effects of Xabine tablets include:

• diarrhea
• hand and foot syndrome
• nausea
• vomiting
• stomach-area (abdominal) pain
• tiredness
• weakness
• increased amounts of red blood cell breakdown products (bilirubin) in your blood

These are not all the possible side effects of Xabine tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Xabine tablets?

• Store Xabine tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep Xabine tablets in a tightly closed container.
• Keep Xabine tablets and all medicines out of the reach of children.

General information about the safe and effective use of Xabine tablets.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Xabine tablets for a condition for which it was not prescribed. Do not give Xabine tablets to other people, even if they have the same symptoms you have. It may harm them.

You can ask your pharmacist or doctor for information about Xabine tablets that is written for health professionals.

For more information, go to www.amneal.com or call 1-877-835-5472.

What are the ingredients in Xabine tablets?

Active ingredient: Xabine, USP

Inactive ingredients: anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and purified water. The peach or light peach film-coating contains iron oxide red, iron oxide yellow, macrogol, polyvinyl alcohol, talc and titanium dioxide.

XELODA^® is a registered trademark of Hoffmann-La Roche Inc.

For full TAXOTERE prescribing information, please refer to TAXOTERE Package Insert.

This Patient Information has been approved by the U.S. Food and Drug Administration.

All trade names drug products are the property of their respective owners.

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 03-2017-01

Xabine pharmaceutical active ingredients containing related brand and generic drugs:

• Capecitabine

Xabine available forms, composition, doses:

• Tablets; Oral; Capecitabine 500 mg

Xabine destination | category:

• Human:
• Antineoplastic agents
• Cytotoxic chemotherapy

Xabine Anatomical Therapeutic Chemical codes:

• L01BC06 - Capecitabine

Xabine pharmaceutical companies:

• Ranbaxy

References

1. Dailymed."CAPECITABINE TABLET [AMNEAL PHARMACEUTICALS LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."CAPECITABINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "CAPECITABINE". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Xabine after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Xabine not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology