Data Sheet

Orzel™

(UFT^® capsules plus calcium folinate tablets)

Presentation

Orzel™ is an orally administered dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine anticancer therapy composed of UFT (tegafur 100 mg/uracil 224 mg) capsules co-packaged with calcium folinate (15 mg) tablets.

UFT

UFT is composed of a fixed combination of tegafur, a prodrug of 5-fluorouracil (5-FU), and uracil in a 1:4 molar ratio. UFT capsules are opaque, hard gelatin capsules with a white cap and white body. Each capsule contains 100 mg tegafur and 224 mg uracil.

Tegafur

Tegafur, chemical name 5-fluoro-1-(2-tetrahydrofuryl)-2,4(1 H,3 H )-pyrimidinedione, empirical formula C₈H₉FN₂O₂, is a racemate (50:50 mixture) of the (R)- and (S)-isomers. Its molecular weight is 200.17.

Tegafur is a white off-white crystalline powder, soluble in methanol, and sparingly soluble in water and ethanol.

Uracil

Uracil has the chemical name 2,4(1 H,3 H )-pyrimidinedione and the empirical formula C₄H₄N₂O₂. Its molecular weight is 112.09.

Uracil occurs as a white to off-white crystalline powder, slightly soluble in water, methanol, and ethanol.

Each UFT capsule contains the following inactive ingredients: low-substituted hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell is composed of gelatin and has the marking TC434.

Calcium Folinate

Calcium folinate tablets are peach-colored, round, and scored. They each contain 15 mg of leucovorin (equivalent to 16.2 mg of anhydrous calcium folinate ). The codes BMS and 0131 are engraved above and below the score mark, respectively, on one side of the tablet. The other side of the tablet is plain.

Calcium folinate has the chemical name of L-Glutamic acid, N -[4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexa-hydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-,calcium salt (1:1). The molecular weight of calcium folinate is 511.51.

Calcium folinate is a mixture of the diastereoisomers of 5-formyl derivative of tetrahydrofolic acid. Calcium folinate is a white to light yellow crystalline powder, sparingly soluble in water and slightly soluble in organic solvents.

Each calcium folinate tablet contains the following inactive ingredients: lactose, magnesium stearate, cellulose-microcrystalline, starch-pregelatinized maize, iron oxide-red, and sodium starch glycolate.

Uses

Actions

UFT is an anticancer drug composed of a fixed molar ratio (1:4) of tegafur and uracil to be administered concurrently with calcium folinate. Tegafur is an orally administered prodrug of 5-FU, and uracil reversibly inhibits the primary catabolic enzyme for 5-FU, DPD. Calcium folinate enhances the cytotoxicity of 5-FU by the actions of one of its intracellular metabolites, 5,10-methylenetetrahydrofolate (CH₂FH₄). The independent actions of uracil and calcium folinate provide for dual-biomodulation of tegafur.

The mechanism of cytotoxicity of 5-FU generated from tegafur is similar to that of 5-FU administered directly. Importantly, 5-FU itself is a prodrug that must undergo intracellular activation into its active metabolites, 5-fluoro-deoxyuridine-monophosphate ((FdUMP) and 5-fluorouridine-triphosphate (FUTP), to be cytotoxic. FdUMP inhibits DNA synthesis by forming inhibitory ternary complexes with thymidylate synthetase (TS) and reduced intracellular folates. FUTP is integrated into cellular RNA resulting in the disruption of RNA function. Following competitive inhibition of DPD by uracil, plasma concentrations of 5-FU derived from tegafur are elevated, resulting in high intratumoral exposure to cytotoxic 5-FU anabolites compared to tegafur administration alone. The addition of uracil to tegafur results in higher 5-FU concentrations in tumor tissue versus normal surrounding tissue compared to tegafur dosing alone. In the presence of therapeutic intracellular concentrations of CH₂FH₄ generated from calcium folinate, the binding of FdUMP with TS is rapid and the ternary inhibitory complex is stabilized, disassociating at a significantly slower rate than at physiologic intracellular reduced folate concentrations.

Pharmacokinetics

Doses of Orzel are expressed by the milligram (mg) content of tegafur administered. The single dose and steady-state plasma pharmacokinetics of Orzel were evaluated in 18 patients with colorectal cancer. Following a single dose of UFT (100 to 400 mg), plasma exposures of tegafur increase proportional to dose. Uracil and 5-FU peak plasma concentrations (Cmax) increase in a roughly proportional manner, whereas AUCs increase more than proportionally to dose. Single-dose calcium folinate (25 mg) resulted in maximal plasma concentrations of d,1-folinic acid and 5-methyltetrahydrofolate of 402 ng/mL and 345 ng/mL, respectively. Following UFT 300 mg/m²/day, in three divided doses, tegafur plasma concentrations of > 1000 ng/mL are maintained throughout each 8-hour dosing interval, whereas uracil concentrations decline rapidly following Cmax. 5-FU plasma concentrations peak 30 to 60 minutes after Orzel administration, at approximately 200 ng/mL, and remain detectable (>1 ng/mL) for each 8-hour dosing interval. No significant accumulation of tegafur, uracil, or 5-FU occurs over a 28-day course of Orzel therapy. With chronic oral administration of calcium folinate (75-90 mg/day) as three equally divided doses, plasma concentrations of d,1-folinic acid and 5-methyltetrahydrofolate (100 ng/mL are maintained.

Absorption

Following Orzel administration, tegafur, uracil, and calcium folinate are rapidly absorbed into the systemic circulation. Peak plasma concentrations of tegafur, uracil, 5-FU and d,1-folinic acid are typically achieved within 1 to 2 hours of dosing. The rate of absorption of R-tegafur and S-tegafur are comparable following oral administration of Orzel in cancer patients. Concurrent administration of oral calcium folinate with UFT does not significantly alter the plasma pharmacokinetics of tegafur, uracil, or 5-FU. Similarly, UFT does not affect the oral absorption of calcium folinate. Following a high-fat meal, plasma AUC for uracil and 5-FU were 66% and 37% lower, respectively, compared to Orzel administration under fasting condition. Plasma tegafur AUC was not significantly altered. Peak plasma concentrations were reduced and delayed for tegafur, uracil and 5-FU. Plasma AUC for d,1-folinic acid and 5-methyltetrahydrofolate were 61% and 46% higher following a high-fat meal relative to fasting conditions. (See Dosage and Administration ).

Distribution

Serum protein binding of tegafur is 52% and binding of uracil to serum proteins is negligible. Once absorbed, calcium folinate enters the general pool of circulating reduced folates.

Metabolism

Conversion of tegafur to 5-FU occurs via C-5' oxidation by microsomal enzymes and C-2' hydrolysis by cytosolic enzymes. Microsomal oxidation of tegafur is mediated, to some extent, by human cytochrome P450 2A6. The cytosolic enzymes responsible for the metabolism of tegafur are not known. Other metabolic products of tegafur include 3'-hydroxy tegafur, 4'-hydroxy tegafur, and dihydro tegafur, which are all significantly less cytotoxic than 5-FU. The metabolism of 5-FU formed from tegafur follows the intrinsic de novo pathways for the naturally occurring pyrimidine, uracil.

Excretion

Less than 20% of administered tegafur is excreted intact into the urine following oral administration. The terminal elimination half-lives of tegafur (as the racemate) and uracil following oral administration of Orzel are approximately 11 hours and 20-40 minutes, respectively. The terminal plasma half-life for S-tegafur (10.3 hours) is 4.4-fold longer relative to R-tegafur (2.4 hours). The three hydroxy metabolites of tegafur are eliminated in the urine.

Special Populations

Age, Gender and Ethnicity

Clinical studies evaluating the effects of age, gender, or race on the pharmacokinetics of Orzel have not been performed. A pooled analysis of pharmacokinetic data from 46 patients who received single-dose Orzel did not reveal clinically relevant differences between males (26) versus females (20) or between Caucasians (39) versus non-Caucasians (7). Similarly, no clinically significant associations between patient age (26 to 81 years) and Orzel plasma pharmacokinetics were apparent from this pooled analysis. (See Warnings and Precautions ).

Hepatic Insufficiency

Studies or Orzel disposition in patients with varying degrees of hepatic impairment have not been performed. In a pooled analysis of 46 patients (30 with hepatic metastases) who received single oral doses of Orzel, no significant differences in the plasma exposures of tegafur, uracil, or 5-FU were noted for patients with hepatic metastases compared to patients with no apparent liver involvement. (See Warnings and Precautions ).

Renal Insufficiency

Clinical studies evaluating the impact of renal impairment on the disposition of Orzel in cancer patients have not been performed. (See Warnings and Precautions ).

Clinical Trials

Two randomized Phase 3 multicenter trails were conducted in patients with metastatic colorectal cancer in which the safety and efficacy of Orzel ( UFT capsules plus calcium folinate tablets ) were compared to those of intravenous 5-FU/leucovorin. In both of these studies, patients could have received prior adjuvant treatment for their disease, but this therapy must have been completed at least 6 months before study enrollment. These patients had not received chemotherapy for clinically apparent metastatic disease.

Study CA146-111

The primary endpoint for study CA146-111 was survival. A total of 816 patients with metastatic colorectal cancer wee enrolled in this study, with 409 patients in the Orzel arm and 407 patients in the 5-FU/ calcium folinate. The distribution of disease characteristics at diagnosis was similar between the arms; 307 (75%) and 300 (74%) patients had a primary diagnosis of colon cancer in the Orzel and 5-FU/ calcium folinate, respectively. The remaining patients had a primary diagnosis of rectal cancer (18% for Orzel and 20% for 5-FU/leucovorin) or colorectal cancer (7% for Orzel and 6% for 5-FU/ calcium folinate ). Most patients (80%) had received no prior adjuvant therapy for their disease; of the patients who had received prior adjuvant therapy, 82% had received intravenous 5-FU either alone or in combination with other agents.

In this study, Orzel ( UFT 300 mg/m²/day PO plus calcium folinate 75 or 90 mg/day PO) administered for 28 days followed by 7 days off treatment was compared to 5-FU (425 mg/m²/day IV) plus calcium folinate (20 mg/m²/day IV) administered for 5 days followed by 23 days off treatment.

Study CA146-012

The primary objective for study CA146-012 was to compare the study therapies for their effect on time to progression. A total of 380 patients with metastatic colorectal disease were randomized in this study, with 190 patients in each treatment arm. The distribution of disease characteristics at diagnosis was similar between the arms; 112 (59%) and 122 (64%) of patients had a primary diagnosis of colon cancer in the Orzel and 5-FU arms, respectively. The remaining patients in this study had a primary diagnosis of rectal cancer (39% for Orzel and 33% for 5-FU) or colorectal cancer (2% for Orzel and 3% for 5-FU/ calcium folinate ). Most patients (77%) had received no prior adjuvant therapy for their disease. Of the patients who had received prior adjuvant therapy, 66% received intravenous 5-FU alone or in combination with other agents.

In this study, Orzel (UFT 300 mg/m²/day PO plus calcium folinate 90 mg/day PO) administered for 28 days followed by 7 days off treatment was compared to 5-FU (425 mg/m²/day IV) plus calcium folinate (20 mg/m²/day IV) administered for 5 days followed by 30 days off treatment.

The median survival time for the Phase 3 studies combined was 12.4 months (95% CI: 11.3-13.4 months) for the 599 Orzel-treated patients and 12.6 months (95% CI: 10.9-13.9 months) for the 597 5-FU/LV-treated patients (p=0.084; stratified by study). The hazard ratio (95% CI; stratified by study) for survival 5-FU/LV: Orzel was 1.013 (0.892-1.152).

The adverse event profile of the patients who received Orzel in the Phase 3 metastatic colorectal cancer studies is described in the Adverse Effects section in tabular (Tables 2-3) and narrative form.

Indications

Orzel ( UFT capsules plus calcium folinate tablets ) is indicated for the first-line treatment of metastatic colorectal cancer.

Dosage and Administration

Treatment of Metastatic Colorectal Cancer

The usual dose of Orzel is 300 mg/m²/day UFT plus 90 mg/day calcium folinate (30 mg/dose) administered in three divided doses (every 8 hours) orally one hour before or one hour after meals for 28 consecutive days. If the total number of UFT capsules cannot be evenly divided, the highest dose should be given in the morning and lower doses in the afternoon or evening. Courses may be repeated every 35 days. If doses are missed or the medication is interrupted by the physician, missed doses are not made up during the course. Treatment is not usually extended beyond day 28 within a course. Calcium folinate tablets should be taken at the same time as UFT capsules. Table 1 presents the total daily dose by body surface area (BSA) and the number of capsules/tablets to be taken per day.

Dose Modification Guidelines

Toxicity due to Orzel may be managed using the UFT dose modification scheme described in Table 2. Calcium folinate dose remains unchanged. If the UFT treatment is interrupted, calcium folinate treatment should also be interrupted.

In the event that because of rounding of doses, a patient who receives a dose reduction according to Table 2 would receive the same dose using BSA calculations (Table 1), subsequent treatment should be decreased by 1 UFT capsule per day.

Retreatment within a course or at the start of the next course should be withheld until evidence of hematologic recovery (i.e., granulocyte count ≥1500/mm³ and platelet count ≥100,000/mm³) and recovery of all non-hematologic toxicities to baseline or (CTC grade 1. In the event of CTC grade 2 non-hematologic toxicity, no adjustment in the UFT dose should be made. For CTC grade 3 or 4 non-hematologic toxicity, UFT is reduced by 50 mg/m²/day for the completion of the current course and subsequent courses.

Contraindications

Orzel is contraindicated in patients who have experienced hypersensitivity to UFT, 5-FU, calcium folinate, or any component of the formulations.

Warnings and Precautions

Pregnancy Category D

As with other cytotoxic drugs, Orzel can cause fetal harm when administered to a pregnant woman. UFT is teratogenic in mice, rats and rabbits. There is no specific experience with Orzel in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Orzel. If Orzel is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

General

Patients receiving therapy with Orzel should be monitored by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not require permanent discontinuation, although doses may need to be withheld or reduced (see Dosage and Administration section).

Orzel should be used with caution in patients with myelosuppression, renal or hepatic impairment, symptoms of bowel obstruction, or a history of heart disease.

Myelosuppression

Orzel administration may cause myelosuppression in some patients, This possibility should be considered when evaluating infection or fever in patients undergoing treatment.

Renal Insufficiency

There is little experience with Orzel in patients with renal impairment. Physicians should exercise caution when Orzel is administered to such patients (see Uses )

Hepatic Insufficiency

Because hepatic disorders, including fatal fulminant hepatitis, have been reported in patients receiving UFT, hepatic function tests should be monitored periodically in patients receiving Orzel.

Patients with mild to moderate hepatic dysfunction should be carefully monitored by liver function tests when Orzel is administered. The effect of severe hepatic dysfunction on the disposition of Orzel is not known (see Uses ).

Diarrhoea

Orzel can induce diarrhoea. If Common Toxicity Criteria (CTC) grade 2 or greater diarrhoea occurs, interruption of Orzel should be considered with supportive care initiated as indicated. Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement to avoid the potentially fatal complications of dehydration. (See Dosage and Administration ).

Symptoms of Bowel Obstruction

Oral medications, including Orzel, should be used with caution in patients with symptoms of bowel obstruction.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

UFT was not mutagenic in bacterial strains ( Salmonella and Escherichia ) but did induce chromosomal aberrations in Chinese Hamster Ovary cells and was genotoxic (capable of causing chromosome or mitotic spindle damage) in a rat bone-marrow micronucleus test.

Long-term studies in animals to evaluate the carcinogenic potential of ORZEL have not been conducted.

Use During Lactation

UFT is excreted in breast milk in rats. It is not known whether ORZEL is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, the use of ORZEL in lactating women is not recommended; breast-feeding should be discontinued before taking ORZEL.

Paediatric Use

Safety and effectiveness of ORZEL in paediatric patients have not been established.

Geriatric Use

Approximately 45% of the patients who received ORZEL in clinical trials were ≥65 years of age, and approximately 26% of these patients were ≤75 years of age. No clinically relevant differences in safety or effectiveness were observed between these subjects and younger subjects, although older patients receiving ORZEL tended to have a higher incidence compared to younger patients of any anemia, diarrhoea, and stomatitis/mucositis. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In general, treatment for an elderly patient should be given cautiously, reflecting the greater frequency of (but not statistically significant) decrease in hepatic, renal or cardiac function and of concomitant disease or other drug therapy. (See USES ).

Adverse Effects

The safety advantages observed with Orzel ( UFT capsules plus calcium folinate tablets ) were achieved despite the fact that Orzel-treated patients required significantly fewer concomitant medications to manage their side effects compared to the 5-FU/LV-treated patients in the controlled clinical trials. In both studies, antiemetic use was significantly higher (p<0.001) in patients treated with 5-FU/LV (CA146-011, 72%; CA146-012, 65%) than in patients treated with Orzel (CA146-011, 47%; CA146-012, 38%). In study CA146-011, the use of both systemic anti-infectives and haematopoietic growth factors was significantly higher (p<0.001) in the 5-FU/LV-treated patients. In the 5-FU/LV treatment arm, 51% of the patients were treated with systemic anti-infectives and 8% of the patients received growth factors compared to 37% and <1% of patients, respectively, in the Orzel treatment arm. In study CA146-012, the use of systemic anti-infectives and haematopoietic growth factors was higher for those patients treated with 5-FU/LV than those receiving Orzel, but these differences were not statistically significant.

The safety data are based on the experiences of 1175 patients with metastatic colorectal carcinoma who received treatment in the two Phase 3 studies (see Tables 3 and 4). Table 3 shows important non-haematologic adverse events that occurred in (5% of patients treated in the Phase 3 metastatic colorectal carcinoma studies. 

Table 4 contains important hematologic adverse events that occurred in ≥ 5% of the patients who were enrolled in the two Phase 3 metastatic colorectal cancer studies.

Other Adverse Drug Reactions Observed in Clinical Trials

The following listing includes all those adverse events that were reported as severe and clinically relevant in at least 1% of the 594 patients who received Orzel in the phase 3 metastatic colorectal cancer studies. Only those events that do not appear previously are listed (%):

Intestinal obstruction (3.5), dehydration (3.4), back pain (2.9), dyspnea (2.7), anorexia (2.5), constipation (2.4), pain (1.5), peripheral edema (1.5), arthralgia (1.3), weight decrease (1.2), confusion (1.2), cachexia (1.0), deep thrombophlebitis (1.0) and heart arrest (1.0).

Adverse events that were reported as severe and clinically relevant in less than 1% of patients who received Orzel in the phase 3 metastatic colorectal cancer studies included: arrhythmia, congestive heart failure, myocardial infarction, shock, enteritis, hepatitis, liver failure, gastritis, ileitis, intestinal perforation and abnormal kidney function.

Postmarketing Events

UFT as a single agent is marketed in several countries. In these countries, UFT is given for the treatment of a broad variety of solid tumors using different schedules and doses than were used in the Orzel phase 3 metastatic colorectal cancer studies. In Japan, postmarketing experience with UFT alone in over 20,000 patients has documented the safety of the drug. Postmarketing reports have described clinically important events with UFT; however, the relevance of these reports describing single-agent UFT therapy to experience with Orzel is not clear, since the safety profile of oncology drugs is very schedule dependent. Causality assessment was not provided with the majority of these reports.

The following clinically relevant adverse events have been received in postmarketing reports for UFT. Only those events that are not described in the Orzel clinical trial experience are noted.

Body as a Whole:

Malaise, photosensitivity.

Cardiovascular System:

Angina.

Digestive System:

Acute pancreatitis, fulminant hepatitis, gastric/duodenal ulcer, hepatic cirrhosis.

Nervous System:

Disturbances of consciousness, extrapyramidal symptoms, gait disturbance, leukoencephalopathy, memory loss, paralysis in the extremities and speech disturbance.

Respiratory System:

Interstitial pneumonia.

Skin and Appendages:

Discoid lupus erythematosus-like eruption, skin dyscrasia (including nail abnormalities, blistering and dermatitis), and urticaria.

Special Senses:

Anosmia, alteration in or loss of taste.

Urogenital System:

Acute renal failure, nephrotic syndrome and urinary incontinence.

Interactions

Drugs Metabolized by Cytochrome P450 Enzymes

In vitro studies indicate that tegafur is metabolized, to some extent, by human cytochrome P450 2A6. ORZEL should be administered with caution when used concomitantly with drugs that are substrates or inhibitors of CYP2A6. Neither tegafur nor uracil significantly inhibits the in vitro activity of the two major cytochrome P450 enzymes involved in drug biotransformation (CYP3A4 and CYP2D6). Furthermore, tegafur is not metabolized by human cytochrome P450 isozymes 1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro, suggesting a low likelihood of interactions with substrates, inhibitors, or inducers of these cytochrome P450 enzymes.

Overdosage

Overdosage of ORZEL (UFT capsules plus calcium folinate tablets) could lead to fatal complications. Anticipated manifestations might include nausea, vomiting, diarrhoea, gastrointestinal ulceration and bleeding, bone marrow suppression (including thrombocytopenia, leukopenia, and agranulocytosis). No specific antidote is available; supportive care should be administered.

Medicine Classification

Prescription medicine

Pharmaceutical Precautions

Procedures for the proper handling and disposal of anticancer drugs should be followed. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Package Quantities

Each carton of ORZEL (UFT capsules plus calcium folinate tablets) contains a 7-day supply of UFT (tegafur/uracil capsules) and calcium folinate tablets. Each carton contains two HDPE bottles as described in Table 5. 

Storage

Store below 30°C.

Name and Address:

Pacific Pharmaceuticals Ltd
P O Box 11-183
Ellerslie
AUCKLAND

Telephone: 09 579-2792

Date of Preparation:

13^th October 2005