Tegafur + Gimeracil + Oteracil

Oral
Gastric cancer

CrCl (mL/min)	Dosage
<30	Not recommended.
30-50	20 mg/m2 (expressed as tegafur content) bid.

Severe: Not recommended.

History of severe and unexpected reactions to fluoropyrimidine therapy. DPD deficiency, severe bone marrow suppression (e.g. neutropaenia, leukopaenia or thrombocytopaenia), ESRD requiring dialysis. Pregnancy and lactation. Concomitant use w/ other fluopyrimidines and use w/in 4 wk treatment of DPD inhibitors.

Severe hepatic and renal impairment (CrCl <30 mL/min).

Significant: Bone marrow suppression (e.g. neutropaenia, leukopaenia, thrombocytopaenia, anaemia and pancytopaenia), acute renal failure, diarrhoea, dehydration, electrolyte disturbance, lacrimal disorders (e.g. increased lacrimation, dry eye, dacryostenosis).
Nervous: Peripheral neuropathy, dizziness, headache, fatigue, asthenia, insomnia.
CV: Hypotension, DVT, HTN, peripheral oedema.
GI: Nausea, vomiting, anorexia, dysgeusia, stomatitis, dry mouth, flatulence, dyspepsia, abdominal discomfort/pain, dysphagia, GI inflammation, GI haemorrhage.
Resp: Dyspnoea, epistaxis, hiccups, cough.
Hepatic: Hyperbilirubinaemia, increased ALT and AST.
Genitourinary: Hyperuricaemia.
Endocrine: Wt loss.
Musculoskeletal: Musculoskeletal pain.
Otic: Hearing impairment, deafness.
Ophthalmologic: Vision disorders (e.g. blurred vision, diplopia, photopsia, decreased visual acuity, blindness), conjunctivitis.
Dermatologic: Palmar-plantar erythrodysaesthesia syndrome, rash, pruritus, hyperpigmentation, dry skin, alopecia.
Others: Mucosal inflammation, pyrexia, chills.

This drug may cause blurred vision, dizziness, fatigue and nausea, if affected, do not drive or operate machinery.

Monitor haematology, renal (e.g. serum creatinine, CrCl) function, hepatic function and serum electrolytes.

Symptoms: Nausea, vomiting, diarrhoea, mucositis, GI irritation, bleeding, bone marrow depression and resp failure. Management: Supportive treatment.

Increased risk of bleeding w/ coumarin-derivative anticoagulants. Increased myelotoxicity and haematologic toxicity w/ clozapine. Increased adverse effects and toxicities w/ cimetidine, folinic acid metabolites, methotrexate and nitroimidazoles. Decreased efficacy w/ CYP2A6 inhibitors and allopurinol. Increased plasma concentration and toxicity w/ phenytoin.
Potentially Fatal: Increased serum level concentration and toxicities w/ other fluoropyrimidines (e.g. capecitabine, flucytosine, 5-FU) and DPD inhibitors (e.g. sorivudine, brivudine).

Decreased exposure of gimeracil and oteracil.

Description:
Mechanism of Action: Tegafur: Tegafur, a fluoropyrimidine antimetabolite agent, is a prodrug of 5-fluorouracil which forms an active metabolite, 5-fluoro-deoxyuridine-monophosphate (FdUMP). FdUMP and reduced folate binds to thymidylate synthase forming a ternary complex leading to inhibition of DNA synthesis.
Gimeracil: Gimeracil inhibits dihydropyrimidine dehydrogenase (DPD), the main enzyme degrading 5-FU, thereby increasing 5-FU exposure and anti-tumour activity.
Oteracil: Oteracil inhibits orotate phosphoribosyltransferase (OPRT), an enzyme thought to play a role in the GI toxicity of 5-FU, thereby decreasing toxicity of 5-FU in GI mucosa.
Pharmacokinetics:
Absorption: Tegafur: Well absorbed from the GI tract. Time to peak plasma concentration: 0.5-0.8 hr; 2 hr (5-FU).
Gimeracil: Time to peak plasma concentration: 1 hr.
Oteracil: Time to peak plasma concentration: 2 hr.
Distribution: Tegafur: Crosses blood-brain barrier and distributed in the CSF. Volume of distribution: 16 L/m². Plasma protein binding: 52.3%; 18.4% (5-FU).
Gimeracil: Volume of distribution: 17 L/m². Plasma protein binding: 32.2%.
Oteracil: Distributed into GI tract tissues. Volume of distribution: 23 L/m². Plasma protein binding: 8.4%.
Metabolism: Tegafur: Metabolised in the liver by CYP2A6 into 5-FU which is further metabolised via phosphorylation into FdUMP (active).
Excretion: Tegafur: Via urine (3.8-4.2% as unchanged drug, 9.5-9.7% as 5-FU). Elimination half-life: 6.7-11.3 hr; 1.6-1.9 hr (5-FU).
Gimeracil: Via urine (65-72% as unchanged drug). Elimination half-life: 3.1-4.1 hr.
Oteracil: Via urine (3.5-3.9% as unchanged drug). Elimination half-life: 1.8-9.5 hr.

Source: National Center for Biotechnology Information. PubChem Database. Tegafur, CID=5386, https://pubchem.ncbi.nlm.nih.gov/compound/Tegafur (accessed on Jan. 23, 2020)

Source: National Center for Biotechnology Information. PubChem Database. Gimeracil, CID=54679224, https://pubchem.ncbi.nlm.nih.gov/compound/Gimeracil (accessed on Jan. 23, 2020)

Source: National Center for Biotechnology Information. PubChem Database. Oxonic Acid, CID=4604, https://pubchem.ncbi.nlm.nih.gov/compound/Oxonic-Acid (accessed on Jan. 23, 2020)

This is a cytotoxic drug. Any unused portions should be disposed of in accordance w/ local requirements.

Cytotoxic Chemotherapy

Buckingham R (ed). Gimeracil. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/08/2017.

Buckingham R (ed). Oteracil. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/08/2017.

Buckingham R (ed). Tegafur. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/08/2017.

Joint Formulary Committee. Tegafur with Gimeracil and Oteracil. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/08/2017.

Teysuno 15 mg/4.35 mg/11.8 mg and 20 mg/5.8 mg/15.8 mg Hard Capsules (Nordic Group BV). European Medicines Agency [online]. Accessed 15/08/2017.