thioguanine

Trade Name:

Lanvis®

Appearance:

Greenish-yellow tablet

Monograph Name:

thioguanine

Monograph Body:

Drug Monograph

A - Drug Name

thioguanine

COMMON TRADE NAME(S): Lanvis®

B - Mechanism of Action and Pharmacokinetics

It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase).

Absorption

Oral: Variable and incomplete, 14 - 46% (mean 30%) bioavailability

Distribution

Not completely elucidated, crosses the placenta

Cross blood brain barrier?

Trace

PPB

No information found

Metabolism

Predominantly in liver and other tissues; extensively metabolised by methylation, oxidation and deamination. Metabolism is not inhibited by xanthine oxidase inhibitors.

Active metabolites

2-amino-6-methylmercaptopurine

Inactive metabolites

yes

Elimination

Mainly in urine

Urine

24-46% within 24 hours (little unchanged)

Half-life

5 - 9 hours

C - Indications and Status

Health Canada Approvals:

Acute leukemia

D - Adverse Effects

Emetogenic Potential:

Minimal – No routine prophylaxis; PRN recommended

The following adverse effects include those reported for use of thioguanine as a component of combination chemotherapy, so some of these effects may be due to other chemotherapy drugs.

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Dermatological	Photosensitivity (rare)	E
	Rash (rare)	E
Gastrointestinal	Anorexia (less common)	E
	Colitis (rare)	E D
	Diarrhea (common)	E
	GI perforation (rare)	E
	Mucositis (common)	E
	Nausea, vomiting (less common)	I
Hematological	Myelosuppression ± infection, bleeding (common, includes pancytopenia; may be severe - nadir 7-14 days, recovery 21 days)	E
Hepatobiliary	↑ LFTs (may be severe)	E
	Portal hypertension (may be severe)	E
	Veno-occlusive disease (may be severe)	E
Metabolic / Endocrine	Hyperuricemia (during periods of active cell lysis - common)	I

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

The primary toxicity of thioguanine is dose-related myelosuppression.

Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (e.g., some leukemias and lymphomas) can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.

Unlike mercaptopurine, thioguanine's metabolism is not inhibited by the xanthine oxidase inhibitor allopurinol. However, toxicity is markedly increased in patients with inherited deficiencies of TPMT and HGPRT.

Prolonged maintenance use may be associated with veno-occlusive disease or portal hypertension, with thrombocytopenia and abnormal liver function tests and is common in children and males. In some cases, portal hypertension may persist for 5 to 9 years after treatment cessation. Liver toxicity may be reversible. Nodular regenerative hyperplasia and centrilobular hepatic necrosis has been reported rarely.

Photosensitivity may lead to an increased risk of skin cancer. Patients should limit sun exposure, wear protective clothing and use sunscreen with an SPF ≥ 30.

E - Dosing

Refer to the local protocol by which the patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.

Thioguanine should not be used in patients with mercaptopurine-resistant disease and is not recommended for maintenance treatment due to the high risk of liver toxicity.

Genotypic or phenotypic tests of TPMT are recommended prior to starting treatment as patients with TPMT deficiency may need significant starting dose reductions.

Adults:

Calculate doses to nearest 20 mg. Take as a single dose, on an empty stomach.

Induction:
2 mg/kg/day p.o, may increase to 3 mg/kg/day if no response after 4 weeks

Suggested dose adjustments per TPMT geno/phenotype:

TPMT geno/phenotype	thioguanine dose
Homozygous wild type or high activity (2 functional *1 alleles)	No change in starting dose. Adjust doses per protocol for myelosuppression. Allow 2 weeks to reach steady state after each dose adjustment.
Heterozygous or intermediate activity (one functional 1 allele, plus one non-functional allele 2, 3A, 3B, 3C or 4)	Reduce starting dose by 30-50% and adjust doses per protocol for myelosuppression. Allow 2-4 weeks to reach steady state after each dose adjustment. Reduce thioguanine dose first vs. other drugs.
Homozygous, mutant or low activity (2 non-functional alleles 2, 3A, 3B, 3C or *4)	Reduce starting dose 10-fold and dose 3 times weekly. Adjust dose per protocol for myelosuppression. Allow 4-6 weeks to reach steady state after each dose adjustment. Reduce thioguanine dose first vs. other drugs.

Dosage with Toxicity:

Dosage in Myelosuppression: Modify according to protocol by which patient is being treated.

Dosage with Hepatic Impairment:

Hepatic impairment may increase thioguanine exposure; consider reducing the starting dose. Dose should be held with evidence of hepatotoxicity or biliary stasis.

Dosage with Renal Impairment:

No data are available in renal impairment; consider reducing the starting dose.

Dosage in the elderly:

There are limited safety data in patients aged 65 and older. Dose selection should be cautious, starting at the lower end of the protocol dosing range, reflecting the increased risk with reduced hepatic, renal or cardiac function, co-morbidities and co-administered drugs.

Children:

See specific protocols for doses and dose modifications. Liver toxicity has been observed in children receiving thioguanine as part of maintenance therapy.

F - Administration Guidelines

Oral self-administration; drug available by outpatient prescription.

G - Special Precautions

Contraindications:

Patients with hypersensitivity to this drug or any of its components
Patients those disease has demonstrated prior resistance to this drug or mercaptopurine; thioguanine is cross-resistant with mercaptopurine
Thioguanine is not recommended as maintenance treatment due to the high incidence of liver toxicity and veno-occlusive disease
Live vaccines

Other Warnings/Precautions:

Patients with inherited deficiencies of thiopurine methyltransferase (TPMT) or hypoxanthine guanine phosphoribosyltransferase (Lesch Nyhan syndrome) are at risk for excessive toxicity, as are patients taking drugs that inhibit TPMT such as sulfasalazine.

Other Drug Properties:

Carcinogenicity: Yes

Pregnancy and Lactation:

Mutagenicity: Yes
Teratogenicity: Yes
Fetotoxicity: Yes

Thioguanine should not be used in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
Excretion into breast milk: Likely

Breastfeeding is not recommended.
Fertility effects: Likely

H - Interactions

Unlike mercaptopurine, thioguanine’s metabolism is not inhibited by the xanthine oxidase inhibitor allopurinol. It is unclear whether thioguanine dose reduction is required when given in combination with allopurinol.

AGENT	EFFECT	MECHANISM	MANAGEMENT
Busulfan	Hepatotoxicity, esophageal varices, portal hypertension	Unknown	Monitor if given together for long-term therapy
TPMT inhibitors (sulfasalazine, mesalazine, olsalazine	↑ toxicity	↓ TPMT	Caution with concomitant use

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
TPMT geno/phenotype testing	Before starting treatment
CBC	Baseline and at least weekly
Liver function tests	Baseline and at each visit
Renal function tests	Baseline and at each visit
Clinical toxicity assessment for infection, bleeding, GI, skin and liver toxicity	At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

J - Supplementary Public Funding

ODB - General Benefit (ODB Formulary )

thioguanine

K - References

Lanvis® (thioguanine) product monograph. Concord, Ontario; Triton Pharma Inc.; Sept 21, 2017.

June 2019 Updated emetic risk category.

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.

Info Sheet Name:

thioguanine (patient)

Info Sheet Introduction:

• For treating acute leukemia, a type of blood cancer.

Info Sheet Date: Friday, December 8, 2017 Info Sheet body:

Medication Information Sheet

thioguanine (thigh-oh-GWON-een)

This document provides general information about your medication. It does not replace the advice of your health care professional. Always discuss your therapy with your health care professional and refer to the package insert for more details.

Other Name: Lanvis®

Appearance:

Greenish-yellow tablet

What is this medication for?

For treating acute leukemia, a type of blood cancer.

What should I do before I have this medication?

Tell your doctor if you have or had significant medical condition(s), especially if you have any allergies.
People who have cancer are at a higher risk of developing other cancers or blood clots. Also, some cancer medications, such as thioguanine, may increase these risks. You should discuss these with your doctor.
This drug contains a small amount of lactose. If you cannot tolerate lactose, talk to your doctor.

How will this medication affect sex, pregnancy and breastfeeding?

The use of this medication in men or women may cause harm to the unborn baby if pregnancy occurs. Let your health care team know if you or your partner is pregnant, becomes pregnant during treatment, or if you are breastfeeding
► Use 2 effective forms of birth control at the same time while taking this drug. Keep using birth control for at least 6 months after your last dose unless your health care team told you differently. Talk to your health care team to figure out the best method(s) for you and/or your partner.
Do not breastfeed while using this drug.
This medication may affect fertility (ability to get pregnant)

How is this medication given?

Take it exactly as directed by your doctor. Make sure you understand the instructions.

Swallow whole with a glass of water
If you miss a dose, take it as soon as possible, otherwise skip this dose and take your next dose as scheduled. Do not double the dose to make up for the missed dose.

What else do I need to know while on this medication?

This medication can interact with other medications and can result in the treatment not working as well or cause severe side effects.
Make sure your health care team knows about all your medications (prescription, over-the-counter, herbals and supplements). Check with your health care team before starting or stopping any of them.
For mild aches and pain:
- You may take acetaminophen (Tylenol®) tablets. Ask your health care team about the right dose for you.
- Ibuprofen (Advil®, Motrin®), naproxen (Aleve®) or aspirin (acetylsalicylic acid, ASA), including low dose aspirin for heart conditions, may increase your chance of bleeding.
- Talk to your health care team before you start or stop these medications.
- If you feel unwell, take your temperature before taking any of these medications. They may hide a fever.
- Talk to your health care team or go to the closest emergency room right away if you have a fever. See the Fever pamphlet for more information.
Drinking alcohol and smoking during your treatment may increase some side effects and make your medication less effective. Speak to your health care team about smoking and drinking alcohol while on treatment.

How should I safely store this medication?

Keep this medication in the original packaging at room temperature in a dry place, away from heat and light. Keep out of sight and reach of children and pets.
Do not throw out any unused medications at home. Bring them to your pharmacy to be thrown away safely.

What are the side effects of this medication?

The following side effects have been seen in people using thioguanine with other chemotherapy drugs, so some of these effects may be caused by chemotherapy.

You may not have all of the side effects below. You may have side effects that are not listed.

Side effects and what to do	When to contact doctor?
More Common Side Effects

Diarrhea

May happen days to weeks after you get your treatment.

If you have diarrhea :

Take anti-diarrhea medication if your health care team prescribed it.
Avoid foods or drinks with artificial sweetener (e.g. chewing gum, “diet” drinks), coffee and alcohol.
Eat many small meals and snacks instead of 2 or 3 large meals.
Drink at least 6 to 8 cups of liquids each day. Talk to your health care team if you can’t drink 6-8 cups of liquids each day when you have diarrhea. You may need special liquids with salt and sugar, called Oral Rehydration Therapy.

See the Diarrhea pamphlet for more information.

Contact your health care team if no improvement or if severe

Rapid killing of cancer cells when you start treatment

If mild, this may cause gout and joint pains. In some more severe cases, it may cause fevers, kidney problems, confusion and be life-threatening.
Your doctor may prescribe medication to prevent these effects.
Drink plenty of liquids (6 to 8 cups per day, unless you have been told otherwise) and pee frequently.

Get emergency medical help right away

Mouth sores

You may have round, painful, white or gray sores inside your mouth. They can occur on the tongue, lips, gums, or inside your cheeks. In more severe cases they may make it hard swallow, eat or to brush your teeth. They usually last 1 to 2 weeks.

To help prevent mouth sores:

Take care of your mouth by gently brushing and flossing regularly.
Rinse your mouth often. Do not use mouthwashes with alcohol.
Instead, try a homemade mouthwash:
Mix 1 teaspoonful of baking soda and 1 teaspoonful of salt in 4 cups (1L) of water.

If you have mouth sores:

Check with your health care team as soon as you notice mouth or lip sores or if it hurts to swallow.
Avoid hot, spicy, acidic, hard or crunchy foods. Your doctor may prescribe a mouthwash to relieve mouth sores and prevent infection.

See the Mouth Care pamphlet for more information.

Contact your health care team as soon as possible

Unusual bleeding or bruising

You may have black stools, cough up blood, blood in your urine, purple or red dots on your skin or bleeding that will not stop.

Fever, chills, infection

You have a fever if your temperature taken in your mouth (oral temperature) is:

38.3°C (100.9°F) or higher at any time OR
38.0°C (or 100.4°F) or higher for at least one hour.

While you are getting treatment:

Keep a digital thermometer at home and take your temperature if you feel hot or unwell (for example, chills).
Avoid taking medications that treat a fever before you take your temperature (for example, Tylenol®, acetaminophen, Advil® or ibuprofen) as they may hide a fever.
Do not eat or drink anything hot or cold right before taking your temperature.
Wash your hands often.
Check with your doctor before getting any vaccines, surgeries, medical procedures or visiting your dentist.

If you have a fever, talk to your health care team or go to the closest emergency room.
See our Neutropenia (Low white blood cell count) pamphlet for more information.

Get emergency medical help right away

Side effects and what to do	When to contact doctor?
Less Common Side Effects, but may be Severe

Low appetite

You may not feel like eating or you may lose weight.
Try to eat foods that you like and eat small meals throughout the day.
You may need to take meal supplements to help keep your weight up.
Talk to your health care team if you have a low appetite.
See our Loss of appetite pamphlet for more information.

Contact your health care team if no improvement or if severe

Infection of your intestines, tear in your stomach or intestines

You may have severe belly cramps or pain, belly tenderness, diarrhea or blood in your poo.
If you have a fever i.e. your temperature taken in your mouth (oral temperature) is 38.3°C or 100.9°F or higher at any time OR 38.0°C or 100.4°F or higher for at least one hour (fever) speak to your health care team or go to the closest emergency room right away.

Get emergency medical help right away

Nausea and vomiting

May occur in hours to days after your treatment. It is easier to prevent nausea than to treat it if it happens.

To help prevent nausea:

Take anti-nausea medication(s) as prescribed to you by your doctor.
Drink clear liquids and have small meals. Get fresh air and rest.
Do not eat spicy, fried foods or foods with a strong smell.
Limit caffeine (e.g. coffee, tea) and alcohol.

If you have nausea or vomiting:

Take anti-nausea medication(s) as prescribed to you by your doctor.
Contact your health care team if the prescribed anti-nausea medications are not helping to control your nausea and vomiting.

Also see Nausea & Vomiting pamphlet for more information.

Contact your healthcare team if nausea lasts more than 48 hours or vomiting lasts more than 24 hours

Skin sensitivity to sunlight

Your skin may be more sensitive to the sun. You can have an itchy rash and other skin reactions when you are exposed to the sun.

Try to stay out of the sun if you can.
Apply sunscreen with UVA and UVB protection and an SPF of at least 30.
Use a lip balm with sunscreen for your lips.
When you are in the sun, wear long sleeved shirts, long pants and a hat to protect yourself.
Use a daily moisturizer on your skin.

Contact your health care team if no improvement or if severe

Rash; dry, itchy skin

Rash may be severe in some rare cases and cause your skin to blister or peel. If this happens, get emergency medical help right away.

To prevent and treat dry skin,

Use skin moisturizer.
Protect your skin from the sun and the cold.
Use sunscreen with UVA and UVB protection and a SPF of at least 30.

Contact your health care team if no improvement or if severe

Liver problems

It may cause you to gain weight, have a tender (hurts to touch) right side of your belly or have eyes or skin that may look yellow.

You may also have bright red or black/tarry coloured poo, a swollen or painful belly and feel confused or forget things.

Get emergency medical help right away

For more links on how to manage your symptoms go to https://www.cancercareontario.ca/en/symptom-management.

The information set out in the medication information sheets, regimen information sheets, and symptom management information (for patients) contained in the Drug Formulary (the "Formulary") is intended to be used by health professionals and patients for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or side effects of a certain drug, nor should it be used to indicate that use of a particular drug is safe, appropriate or effective for a given condition.

A patient should always consult a healthcare provider if he/she has any questions regarding the information set out in the Formulary. The information in the Formulary is not intended to act as or replace medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.

Info Sheet (English):

thioguanine patient.pdf Info Sheet (French):

thioguanine pour le patient.pdf Monograph:

thioguanine.pdf Funding Program: ODB - General Benefit Funding Instance:

thioguanine

Phonetic Spelling:

thigh-oh-GWON-een

Cancer Type: Hematologic Leukemia - Acute Lymphoblastic (ALL) Type of Content: Drug Monograph Status: Null Info Sheet Status: Null Global Date: Tuesday, June 4, 2019 Universal Date: 2019-06-04 00:00:00 AddThis: Title URL: thioguanine Drug Display Status: Active Revision Summary:

Updated emetic risk category.