Thiotepa
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Vial containing 15mg thiotepa powder for solution for injection
Drugs List
Therapeutic Indications
Uses
Treatment of neoplastic disease, for use alone or in combination with other cytotoxic drugs or with surgery.
Treatment of condyloma acuminata.
Prevention of recurrences of pterygium after surgery.
It is a polyfunctional alkylating agent.
Dosage
Treatment should be administered under the supervision of a qualified physician who is experienced in the use of chemotherapeutic agents.
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Dosing should be carefully individualised. A slow response to thiotepa does not necessarily indicate a lack of effect, therefore increasing the frequency of dosing may only increase toxicity.
Therapy should only be effected under hospital conditions.
Adults
Dosage schedules vary according to the route of administration and the indication.
For intramuscular injection, bladder and intracavitary instillations:
Up to 60mg in single or divided doses. Doses should be reduced in cases of leucopoenia as indicated below:
WBC count/cubic millimetre 6000. Dose of 60mg.
WBC count/cubic millimetre 5000 - 6000. Reduce dose to 45mg.
WBC count/cubic millimetre 4500 - 5000. Reduce dose to 30mg.
WBC count/cubic millimetre 4000 - 4500. Reduce dose to 20mg.
WBC count/cubic millimetre 3500 - 4000. Reduce dose to 10mg.
WBC count/cubic millimetre 3000 - 3500. Reduce dose to 5mg.
WBC count/cubic millimetre below 3000. Omit dose.
Intrathecal injection
Up to a maximum of 10mg.
Breast cancer
Patients with breast cancer have been treated with thiotepa as part of a combination regimen, given intramuscularly in divided doses of 15-30mg three times a week for 2 weeks; this representing one course of treatment. An interval of 6 to 8 weeks is recommended between courses to allow bone marrow recovery.
An alternative schedule employs thiotepa as part of a combination regimen, given as an initial priming dose of 15mg intramuscularly or intravenously each day for 4 days. This may be followed in 3 weeks by maintenance doses of 15mg intramuscularly every 14-21 days.
Bladder cancer
Instillations of thiotepa have been used to treat multiple superficial tumours of the bladder, resulting in a complete clinical response in about one third of patients. Patients are dehydrated for 8-12 hours prior to treatment. Up to 60mg thiotepa dissolved in 60ml sterile water is instilled into the bladder by catheter once a week for 4 weeks. During removal of the catheter following instillation, thiotepa injection is continued to ensure bathing of the prostatic and pendulous urethra.
The solution should be retained for up to 2 hours and the patient should be frequently repositioned to ensure maximum contact with the urothelium.
Patients are generally cystoscoped 2 weeks after a course of four instillations. If a response is observed a second course of four thiotepa instillations may be given, generally at a reduced dosage, e.g. 15-60mg with intervals of 1 to 2 weeks between instillations.
Second and third courses must be given with caution since bone-marrow depression may be increased.
Instillations of thiotepa have been used prophylactically as an adjunct to surgical resection of superficial tumours of the bladder, resulting in a marked decrease in the recurrence rate.
It is recommended that there should be a minimum interval of one week between tumour resection and the commencement of prophylactic instillation of thiotepa. 30-60mg thiotepa dissolved in 60ml sterile water is instilled into the bladder for 2 hours and repeated at intervals of one to two weeks for a total of 4-8 instillations. The initial course may be followed by instillations of thiotepa, 30-60mg every 4 to 6 weeks for one year or longer.
Single dose thiotepa instillations have been used prophylactically as an adjunct of surgical resection in the treatment of superficial tumours of the bladder. 90mg thiotepa dissolved in 100mg sterile water is instilled into the bladder with the patient in the left lateral position. After 15 minutes the patient is transferred to the right lateral position and after a further 15 minutes the bladder is emptied. It is felt that such single dose administration may decrease the incidence of systemic toxicity by decreasing the extent of systemic absorption of the drug.
NOTE: Patients who have had previous radiotherapy to the bladder areat increased risk of drug toxicity.
Malignant meningeal disease
Intrathecal injections of thiotepa have been found to be useful for the palliative treatment of cases of meningeal infiltration by leukaemia and lymphomas.
Thiotepa, at a concentration of 1mg/ml in sterile water is administered by injection through a lumbar theca in doses of up to 10mg on alternate days until there is clearance of malignant cells from the cerebrospinal fluid (CSF). It is recommended that if no improvement occurs in the CSF after three injections, then treatment should be changed.
Not more than 4 injections should be given on alternative days. Routine blood counts should be performed prior to each dose of thiotepa.
Ovarian cancer
Ovarian cancer has been treated with thiotepa as a single agent or as part of a combination regimen in a variety of schedules.
Thiotepa may be given intravenously or intramuscularly daily for 4 days initially and then continued with single doses administered once a week or once every 2 weeks.
Intracavitary instillation
Instillations of thiotepa have been used to treat malignant pleural effusions and abdominal ascites.
The procedure recommended, is first to aspirate as much fluid as possible and then to instil the dose of thiotepa, 10-60mg in 20-60ml sterile water. This may be repeated once a week or once every 2 weeks.
Prevention of recurrences of Pterygium
A 1:2000 solution of thiotepa in sterile Ringer's solution (i.e.15mg powder in 30ml Ringer's), applied topically as eye drops, every three hours daily for up to 6 weeks after surgical removal of the pterygium is effective in reducing the recurrence rate following surgery.
Condyloma Acuminata
Thiotepa applied topically or instilled intraurethrally in a gel, has been successfully used to eradicate condyloma acuminata.
The drug may be administered by first reconstituting 60mg thiotepa with 5ml sterile water. This is diluted to 15ml, using a sterile mixture of water and lubricating jelly made to a consistency viscous enough to remain in the urethra and fluid enough to allow easy injection. This therapy may be repeated at weekly intervals.
Elderly
(See adult dose)
Children
Children over 12 years of age - see adult dose.
Use in children under 12 years of age is not recommended.
Patients with Renal Impairment
Patients with Hepatic Impairment
Additional Dosage Information
Administration
Thiotepa may be given by intravenous, intramuscular and intrathecal routes of injection. It may be given directly into pleural, pericardial or peritoneal cavities and as a bladder instillation.
Luer-Lock fittings should be used on all syringes and sets. Large bore needles or venting needles are recommended to minimise pressure and possible formations of aerosols.
Handling
Standard guidelines on handling cytotoxic drugs should be followed:
1. Trained personnel should reconstitute cytotoxics;
2. Reconstitution should be carried out in designated areas;
3. Protective clothing (including gloves) should be worn;
4. The eyes should be protected and means of first aid should be specified;
5. Pregnant staff should not handle cytotoxics;
6. Adequate care should be taken for the disposal of waste material, including syringes, containers and absorbent material.
Although thiotepa is not a vesicant and should not cause harm if it comes into contact with the skin, it should be washed off immediately. Any transient stinging may be treated with bland cream.
Reconstitution
Thiotepa 15mg should be reconstituted with 1.5ml water for injection immediately prior to use. Reconstituted solutions should be clear to slightly opaque. Solutions that are grossly opaque or precipitated should be discarded.
Reconstituted solutions may be stored in a refrigerator (2-8 degrees C) for 24 hours. Discard if a precipitate forms on storage.
Compatibilities
Thiotepa may be mixed in the same syringe with procaine hydrochloride 2% or with adrenaline 1 in 1,000 or with both.Incompatibilities
Thiotepa is unstable in an acid medium.Precautions and Warnings
Treatment should be administered under the supervision of a qualified physician who is experienced in the use of chemotherapeutic agents.
Whilst the doses stated are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Death from septicaemia and haemorrhage has occurred as a direct result of haematopoietic depression by thiotepa. Death has also occurred after intravesical administration, caused by bone-marrow depression from systemically absorbed thiotepa.
White blood cell and platelet counts are recommended 12-24 hours before each dose of thiotepa, at weekly intervals during therapy and for at least 3 weeks after therapy has been discontinued. (Except when administered as eye drops or to treat condyloma acuminata)
Bone marrow depression may be delayed by up to 30 days post treatment, and myelosuppression may be prolonged.
Dosage should be adjusted according to white blood cell count.
Thiotepa is contraindicated in patients with a white blood cell count below 3,000 cells per cubic mm and/or a platelet count below 100,000 per cubic mm. Treatment should be discontinued if the white cell or platelet count falls rapidly.
Thiotepa should not normally be used in patients with existing hepatic, renal or bone marrow damage. Use in these patient groups should only be considered if the potential benefit outweighs the risk to the patient.
In such cases, the lowest effective dose should be used.
Patients with porphyria (see Use in Porphyria section)
Elderly patients should be treated with caution. Dosing should start at the lowest end of the dosing range.
Safe use in children has not been established.
Women of child-bearing potential age should use effective contraception during treatment.
As thiotepa may adversely affect spermatogenesis, male patients should use effective contraception during treatment and for 1 year following treatment. Male patients should also be advised to consider sperm cryopreservation prior to treatment.
There is some evidence of thiotepa being carcinogenic in humans. Cases of myelodysplastic syndromes and acute non-lymphocytic leukaemia in patients treated with thiotepa.
Since absorption from the gastrointestinal tract is variable, thiotepa should not be administered orally.
Previous brain or craniospinal irradiation may increase severe toxic reactions e.g. encephalopathy.
Prior radiation to the bladder may increase drug toxicity when instilled into the bladder.
Side effects such as dizziness and blurred vision may affect the ability to drive or operate machinery.
St John's Wort may affect plasma level and toxicity of thiotepa- advise patients that they should not self-medicate.
Use in Porphyria
The Norwegian Porphyria Centre (NAPOS) considers thiotepa as a drug which is 'possibly porphyrinogenic'.Pregnancy and Lactation
Pregnancy
Contraindicated for use in pregnancy. Thiotepa may cause foetal harm when administered to pregnant women.
There are no well-controlled studies in pregnant women. Therefore, thiotepa should not normally be administered to women who are pregnant unless the benefit outweighs the risk to the foetus or child.
If thiotepa is used during pregnancy, or if pregnancy occurs during treatment, the patient and partner should be warned of the potential hazard to the foetus.
Thiotepa is teratogenic and embryotoxic in mice and rats and has been reported to interfere with spermatogenesis and ovarian function in rodent species.
The effect of concurrent therapies must also be considered.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Animal data - Teratogenic and embryotoxic in mice and rats
Lactation
There are no data on the excretion of thiotepa in human breast milk. However the low molecular weight suggests that excretion into breast milk is to be expected.
Due to the potential risk to the nursing infant breastfeeding should be discontinued during and for 3 months after treatment.
The effect of concurrent therapies must also be considered.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Drug excreted in breast milk? - Unknown but likely
Effects on Ability to Drive and Operate Machinery
Side effects such as dizziness and blurred vision may affect the ability to drive or operate machinery.
Counselling
Side effects such as dizziness and blurred vision may affect the ability to drive or operate machinery.
Advise patients that they should not take St John's Wort during treatment.
Women of child bearing potential should be advised to use effective contraception during treatment.
Male patients should be advised to consider sperm cryopreservation prior to treatment.
Side Effects
Increased susceptibility to infection
Myelodysplastic syndrome
Non-lymphocytic leukaemia (acute)
Bone marrow depression
Thrombocytopenia
Decreased haematological indices
Thromboembolism
Hypersensitivity reactions
Anorexia
Headache
Dizziness
Periorbital skin depigmentation
Blurred vision
Conjunctivitis
Nausea
Vomiting
Diarrhoea
Abdominal pain
Mucositis
Rash
Contact dermatitis
Alopecia
Haemorrhagic cystitis
Dysuria
Urinary retention
Impaired fertility
Amenorrhoea
Interference with spermatogenesis
Fatigue
Weakness
Febrile reactions
Local pain (injection site)
Skin discolouration
Irritation (localised)
Tumour lysis syndrome
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Reference Sources
British National Formulary, 63rd Edition (2012) Pharmaceutical Press, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia
Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.
Summary of Product Characteristics: Thiotepa Injection. Goldshield plc. Revised August 2010
N.A.P.O.S - The Drug Database for Acute Porphyria
https://www.drugs-porphyria.com/languages/UnitedKingdom/index.php?l=gbr
Last Reviewed 13th July 2010
Last Accessed 6th August 2012
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