Postgrad Med J (1994) 70, 901 - 904
`
`i) The Fellowship of Postgraduate Medicine, 1994
`
`Special Article
`Guideline for the clinical use and dispensing of
`thalidomide
`
`R.J. Powell and J.M.M. Gardner-Medwin
`
`Clinical Immunology Unit, Immunology Department, Queen's Medical Centre, University Hospital,
`Nottingham NG7 2UH, UK
`
`Introduction
`
`In the 1960s thalidomide virtually disappeared
`from clinical use after it was demonstrated that it is
`both a causative agent of severe irreversible
`peripheral neuropathy" 2 and a human teratogen.3'4
`Currently in the UK there are no product licences
`for thalidomide but it can be prescribed on a
`'named patient' basis in accordance with Section
`9(1) of the Medicines Act 1968,5 and its subsidiary
`legislation.6 It is being prescribed by hospital-based
`physicians to a small number of patients who have
`exhausted other therapeutic options. Hospital doc-
`tors who prescribe thalidomide should have the
`necessary expertise in its use and the resources to
`detect subclinical neuropathy. There is the poten-
`tial for an increase in its use in conditions such as
`bone marrow transplantation' and HIV-related
`disease.
`Even in these new areas, thalidomide
`should only become an option when all other
`therapeutic modalities have failed.
`continued,
`This
`albeit
`limited,
`of
`use
`thalidomide
`has
`been
`criticized
`by
`some
`clinicians,9"10 and by individuals
`affected by
`thalidomide" because of the known serious side
`effects of the drug. One of their concerns is that
`there
`are no legal
`restrictions
`or guidelines
`regulating its clinical use. Its current use is subject
`to the requirements of the laws governing the
`supply ofa medicine for a 'named patient' prescrip-
`tion.5'6"2"3 This guideline is designed to promote
`the safest possible clinical use and dispensing of
`thalidomide.
`These recommendations may require revision
`and modification as further clinical experience with
`thalidomide is gained. For that reason it is prefer-
`able that its clinical use should be regulated by
`guidelines rather than by law. However, it cannot
`be overstated that the risks of teratogenicity and
`peripheral neuropathy must be recognized, and
`addressed in each and every patient.
`
`Correspondence: R.J. Powell, F.R.C.P.
`Accepted: 7 July 1994
`
`(A) Clinical use
`
`1. Only severe disabling conditions that cause an
`unacceptable interference with normal life
`should be treated with thalidomide, and only
`after other treatments have been tried and
`failed.
`2. Pregnancy should be excluded before instituting
`therapy with thalidomide, specifically by a
`negative pregnancy test within 2 weeks prior to
`starting therapy.
`3. Patients should be specifically excluded from
`treatment with thalidomide for any of the
`following reasons:
`a. Unwilling to sign a consent form.
`b. Unable to understand the potential risk
`from the use of thalidomide.
`c. Unlikely to be able to comply with the
`prescribing instructions.
`d. Women who wish to become pregnant.
`e. Women of childbearing potential:
`i.
`who have not practised a reliable form
`of contraception for 1 year;
`ii. who are unwilling to take reliable
`contraceptive precautions;
`iii. who are considered not capable of
`complying with the requirements for
`reliable contraception. Reliable con-
`traceptive methods include the contra-
`ceptive pill, an intrauterine device,
`surgical sterilization of patient or sole
`partner. Female patients who do not
`normally practise contraception be-
`cause of a history of infertility should
`do so whilst taking thalidomide.
`4. Fully informed consent should be obtained
`using a written consent form and a signed
`agreement.
`5. Women of childbearing potential should agree
`to stop taking thalidomide immediately should
`they miss a period, and urgently contact their
`prescribing physician. A pregnancy test should
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`

`902
`
`R.J. POWELL & J.M.M. GARDNER-MEDWIN
`
`appropriate
`
`be provided and, if positive,
`counselling should be given.
`6. Women of childbearing potential who discon-
`tinue treatment with thalidomide should agree
`to take reliable contraceptive precautions for 3
`months after discontinuing thalidomide.
`7. Patients should agree to return any unused
`supply of thalidomide
`prescribing
`the
`to
`physician.
`
`(B) Monitoring
`
`1. Appropriate clinical and electrophysiological
`measurements should be recorded before treat-
`ment is commenced. For certain conditions,
`photographs may be useful to monitor the
`progress of treatment.
`2. The anticipated duration of treatment at which
`benefits of therapy will be judged should be
`agreed with the patient and treatment critically
`reviewed at the end of that period. Treatment
`failure must be recognized to avoid unneces-
`sarily extended courses of thalidomide.
`3. Follow-up visits should be at monthly intervals
`or less for the first 3 months to enable the
`clinician to detect side effects/early signs of
`toxicity. The warnings about the possible toxi-
`city and the need for adequate contraception
`should be reinforced. Adequate time should be
`allowed to answer all questions raised by the
`patient.
`4. All adverse events should be recorded and
`serious events notified to the Clinical Trials
`Section, Medicines Control Agency.*
`5. Electrophysiological measurements (see below)
`should be repeated after each 10 g increment in
`total dose or 6 monthly, whichever is the sooner,
`for the duration of therapy.
`6. Patients should be warned, and understand,
`that they must stop thalidomide immediately if
`paraesthesiae develop. In some cases the sen-
`sory loss may be permanent and adequate
`diagnosis, management and follow-up for these
`patients should be arranged.
`
`(C) Electrophysiological measurements
`
`1. Peripheral neuropathy is a common, severe and
`often irreversible side effect of treatment with
`thalidomide. Every effort must be made to
`detect
`this presymptomatically by electro-
`physiological techniques. Unfortunately there
`
`are no published electrophysiological studies
`that outline the criteria to predict the develop-
`ment of paraesthesiae. Should paraesthesiae
`develop, then thalidomide must be stopped
`immediately to limit further damage.
`2. Electrophysiological testing should be per-
`formed at a constant temperature, by a consis-
`tent technique and by the same neurophysio-
`logist, to provide at least one, preferably two,
`pretreatment baseline measurements of sensory
`nerve action potential amplitudes (SNAP). If
`more than one pretreatment value is available,
`confidence limits can be calculated for the
`individual patient.
`3. The SNAP amplitudes should be measured in at
`for example, median,'4
`least
`three nerves,
`radial'5 and sural.'6 A summated score with
`equal weighting for each nerve can be used to
`reduce the dominant contribution from the
`radial nerve SNAP amplitude. Nerve conduc-
`tion velocities would not be expected to show
`significant changes in the early phase of an
`axonal neuropathy.'7
`4. Based on available data, a fall from the baseline
`summated score of > 40% should be regarded
`as significant.'8
`5. For those patients with a fall from baseline
`summated score of between 30% and 40%, the
`intervals should be reduced between measure-
`ments and, therefore, the need to use thalido-
`mide should be reviewed.
`
`(D) Patient information
`
`1. Each patient being treated with thalidomide
`should be given an information sheet (Figure 1).
`2. A doctor prescribing thalidomide on a 'named
`patient' basis is entirely responsible for the
`patient's welfare. He must inform the patient of
`any contraindications, warnings and precau-
`tions associated with the use of the drug. To
`comply with the law,'2 suppliers of a drug for a
`'named patient' prescription must provide in-
`formation about the drug on the containers and
`packages, but are not required to provide
`contraindications, warnings and precautions.
`3. A sample patient information sheet is provided,
`which contains information relating to its pro-
`posed use and warnings about the potential,
`severe side effects of thalidomide. It should be
`updated as required.
`
`(E) Manufacture and dispensing
`
`*Clinical Trial Section, Medicines Control Agency,
`Room 1418 Market Towers, 1 Nine Elms Lane,
`London SW8 5NQ, UK. Tel. 071-273 0327.
`
`1. Thalidomide does not have a product licence in
`the UK. Nevertheless, a manufacturer or sup-
`plier may supply it to a medical practitioner for
`
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`GUIDELINES FOR USE OF THALIDOMIDE
`
`903
`
`PATIENT INFORMATION SHEET FOR THALIDOMIDE USE
`
`in .(patient's name)
`Thalidomide is a drug which can have severe side effects. This means it can only be used to treat a few debilitating
`conditions in which alternative treatments have been tried and failed. Thalidomide must be used with great care
`by patients and doctors and treatment will involve careful monitoring. Despite these drawbacks, in some
`patients thalidomide can be of significant benefit.
`
`Condition being treated ........................................................................................................................................
`
`How is the treatment given, how often and for how long?
`
`Dr
`
`.at
`
`.Hospital
`
`Tel. no . ....................................... has prescribed thalidomide (proprietary name if used) for you.
`
`The dose is .....
`
`mg = .. tablets and should be taken daily at night for .days.
`
`Hospital visits
`
`This treatment is monitored in the out-patients clinic, initially with monthly visits. You will be asked to have an
`electrical nerve test at regular intervals. These nerve tests can cause some discomfort but are an essential aspect
`of monitoring.
`
`Does the drug have side effects?
`
`1. Morning drowsiness is the most noticeable problem. This varies in each individual and may require your
`doctor to reduce the dose. Drowsiness may impair your ability to drive and operate machinery.
`2. Nerve damage: Pins and needles of hands and feet are early signs of nerve damage and can develop after
`repeated courses or regular administration of thalidomide. Should you develop pins and needles you must
`stop thalidomide immediately and contact your hospital doctor. This is not uncommon and can be both severe
`and irreversible.
`The aim ofthe electrical tests is to detect nerve damage before symptoms develop, and these will be a crucial
`part of your follow-up assessments. Should damage become apparent on the nerve test, thalidomide will be
`stopped, halting further deterioration in nerve function. Any damage at this stage would be so small it would
`be unnoticeable, but you would not be given thalidomide again.
`3. Damage to babies: This is very important for all women considering thalidomide. Thalidomide is toxic to the
`developing baby, especially in the early months ofpregnancy. If you wish to consider thalidomide you must
`be prepared to use adequate contraception throughout the duration ofthalidomide therapy and for 3 months
`after it has finished. Should contraception fail, any resulting pregnancy may incur damage to the baby and
`consequently, if you miss a period at any time during treatment, you must stop thalidomide immediately and
`contact the doctor who prescribed the thalidomide. A pregnancy test would then be arranged and
`appropriate counselling given. Should pregnancy be confirmed, further investigations to assess any damage
`to the baby would be indicated. Your doctor can advise you about adequate contraception. No effects on
`male sperm are recognized.
`4. Minor side effects such as constipation, nausea, dizziness, headaches and rarely skin rashes can occur.
`
`Having read this sheet
`
`This treatment involves you in possible risks and benefits. You should not agree to start thalidomide until you
`cleary understand these. Even ifyour doctor recommends the treatment you are free to refuse it and this will not
`in any way influence the rest of your care.
`
`Remember
`Thalidomide is a potentially dangerous medication. It must be securely stored away from children and only
`taken by the person to whom it is supplied.
`
`Figure 1
`
`Patient information sheet for thalidomide use.
`
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`904
`
`R.J. POWELL & J.M.M. GARDNER-MEDWIN
`
`a prescription for a particular patient' ('named
`patient' supply) provided that the manufacturer
`has a manufacturer's licence for 'specials'.'9
`2. Staff and equipment at the manufacturing site
`should be adequate to ensure that the product is
`of the nature and quality specified by the doctor
`or pharmacist. Manufacture should be under
`proper supervision and adequately controlled.
`3. Adequate records should be kept by the manu-
`facturer/supplier. Records should include the
`amount of thalidomide that has been made, the
`form of the finished product, the 'named
`patient', the prescribing doctor and the person
`to whom it has been supplied.
`4. The supplier should satisfy himself beyond
`doubt that orders are from hospital-based con-
`sultants who have knowledge of the use of
`thalidomide and its side effects.
`5. It is recommended that the supplier should
`require that the order should be made in writing
`with the name of the patient, the prescribing
`doctor and the hospital address and telephone
`number. The letter should include a statement
`that the doctor is familiar with the use of
`thalidomide and its
`side effects, including
`peripheral neuropathy and teratogenicity. Also,
`a written assurance should be obtained that the
`drug will only be dispensed by the hospital
`pharmacist to the 'named patient' in accordance
`with the prescription.
`6. Orders to provide a stock for a hospital phar-
`macy should not be accepted. However, an
`amount to provide for 3 months prescription for
`a 'named patient' could be supplied to be held in
`the pharmacy.
`
`References
`
`1. Burley, D. Is thalidomide to blame? Br Med J 1961, 1: 130.
`2. Fullerton, P.M. & Kremer, M. Neuropathy after intake of
`thalidomide (Distaval). Br Med J 1961, 2: 853-858.
`3. McBride, W.G. Thalidomide and congenital abnormalities
`(letter). Lancet 1961, 2: 1358.
`4. Lenz, W. Thalidomide and congenital abnormalities (letter).
`Lancet 1962, 1: 45.
`5. The Medicines Act 1968. HMSO, London, 1968.
`6. The Medicines (Excemption from Licences) (Special Cases
`and Miscellaneous Provisions) Order 1972. HMSO, London,
`1972.
`7. Heney, D., Norfolk, D.R., Wheeldon, J. et al. Thalidomide
`treatment for chronic graft versus-host
`disease. Br J
`Haematol 1991, 78: 23-27.
`8. Makonkawkeyoon, S., Limson-Probre, R.N., Moreira, A.L.,
`Schauf, V. & Kaplan, G. Thalidomide inhibits the replication
`of human immunodeficiency virus type 1. Proc Natl Acad Sci
`USA 1993, 90: 5974- 5978.
`9. Crawford, C.L. Use ofthalidomide in leprosy (letter). Br Med
`J 1991, 302: 1603-1604.
`10. Hawkins,
`D.F.
`Thalidomide
`for
`systemic
`erythematosus (letter). Lancet 1992, 339: 1057.
`11. Drug protest; thalidomide. The Sunday Times 14 April 1991.
`12. The Medicines (Labelling) Regulations ((Regulations 11 (1)
`(b) (i) and 11 (1) (b) (ii)) 1976. HMSO, London, 1976.
`
`lupus
`
`(F) Labelling
`
`1. The labelling of containers and packages for
`medicines supplied for 'named patient' prescrip-
`tions are regulated by law.'2
`2. All particulars should be clear, legible and
`readily discernible so that they can be easily
`read. The particulars to be shown on the
`container should normally be shown on the
`body of the container.
`3. Every container for thalidomide should be
`labelled to show the following information:
`* The non-proprietary name or a proprietary
`designation. In addition the label should
`show a warning: 'Contains thalidomide'.
`* The quantitative
`particulars
`in a con-
`spicuous position. The labelling should dis-
`tinguish between active and non-active
`ingredients.
`* The quantity of thalidomide in the container
`or package.
`* Any special requirements for the handling
`and storage, and the expiry date.
`* The batch reference number, the number of
`the manufacturer's licence (preceded by
`ML), and the name and address of the
`person who manufactured the product.
`* The container should also show the warn-
`ings: 'Do not exceed the staged dose', 'Keep
`out of the reach of children', 'Thalidomide
`causes serious damage to babies if taken by
`women during pregnancy' and 'This drug
`must not be shared with anyone else.'
`
`13. The Medicines (Exemption from Licences) (Importation)
`Order 1984. HMSO, London, 1984.
`14. Gilliatt, R.W. & Sears, T.A. Sensory action potentials in
`patients with peripheral nerve lesions. J Neurol Neurosurg
`Psych 1958, 21: 109-118.
`15. Downie, A.W. & Scott, T.R. An improved technique for
`radial nerve conduction studies. J Neurol Neurosurg Psych
`1967, 30: 332-336.
`16. Burke, D., Skuse, N.F. & Lethlean, A.K. Sensory conduction
`of the sural nerve in polyneuropathy. J Neurol Neurosurg
`Psych 1974, 37: 647-652.
`17. Fullerton, P.M. & O'Sullivan, D.J. Thalidomide neuropathy:
`a clinical electrophysiological and histological follow-up
`study. J Neurol Neurosurg Psych 1968, 31: 543-551.
`18. Gardner-Medwin, J.M.M., Smith, N.J. & Powell, R.J.
`Clinical experience with thalidomide in the management of
`severe oral and genital ulceration in conditions such as
`Behcet's disease: the use of neurophysiological studies to
`detect thalidomide neuropathy. Ann Rheum Dis 1994, 53 (in
`press).
`19. The Medicines (Exemption from Licences) (Special and
`Transitional Cases) Order 1971. HMSO, London, 1971.
`
`CFAD VI 1006-0004
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