2.1 Baseline monitoring prior to commencing valproate
2.2 On-going valproate monitoring
2.3 Therapeutic Drug Monitoring of valproate
levels
2.4 Side-effect monitoring
2.5 Drug-drug interactions
2.6 Valproate shared care guidelines
1
1
2
2
2
3
3 Congenital malformations and development disorders:
3.5 Prescribers checklist
3.5.1 Risk assessment
3.5.2 Capacity assessment
3.5.3 Information provision
3.5.4 Obtaining consent
3.5.5 Risk reduction strategies
3.5.6 Effective contraception
3.6 Patients who refuse information
3.7 Sharing information
4
4
4
5
5
5
6
6
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3.8 Monitoring and follow-up 6
4 Dispensing Valproate
7
5 Further information
7
6 References
8
Appendix – listed within practice guidance note
Document No:
Description Issue Date Issued
Review Date
Appendix 1 Valproate in women of childbearing potential: Prescribers Checklist
Issue-1 Jul 17 Jul 20
Appendix 2 Valproate information booklet for healthcare professionals (Healthcare Professional’s Booklet)
Issue-1 Jul 17 Jul 20
Appendix 3 Valproate information booklet for patients (Patient’s Guide)
Issue-1 Jul 17 Jul 20
Appendix 4 Valproate in women of childbearing potential: Patient Consent Form
Issue-1 Jul 17 Jul 20
Appendix 5 Valproate Patient’s Card Issue-1
Jul 17 Jul 20
Appendix 6 Valproate Side Effect Rating Scale (VSERS)
Issue-1 Jul 17 Jul 20
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1 Introduction
1.1 This Practice Guidance Note (PGN) provides step by step guidance and support for those healthcare professionals within Northumberland, Tyne and Wear NHS Foundation Trust (the Trust/NTW) wishing to prescribe Valproate for either epilepsy/seizure control, mania or mood-stabilisation.
1.2 Valproate is available in the UK in three distinct forms; sodium valproate and
valproic acid (licensed for treatment of epilepsy) and semi-sodium valproate (licensed for treatment of acute mania).
1.3 Valproate (as sodium valproate) is unlicensed for use as a mood-stabiliser, but is
widely used in the UK for this indication. Further guidance on the use of unlicensed medications can be found in section 9, UHM-PGN-02 Prescribing Medicines.
1.4 The Medicines and Healthcare Regulatory Agency (MHRA) advise: do not prescribe
valproate medicines for epilepsy or bipolar disorder in women and girls unless other treatments are ineffective or not tolerated; migraine is not a licensed indication. For further information on the risks associated with congenital malformation and developmental disorders see Section 3 along with specific recommendations on consent and contraception.
2 Prescribing valproate 2.1 Baseline monitoring prior to commencing valproate 2.1.1 The following monitoring should be carried out and recorded in the Core Physical
Health Monitoring Record on RiO:
Allergies
Baseline Full Blood Count (FBC) plus bleeding time and coagulation tests
Liver Function Tests (LFTs)
Weight/Body Mass Index/waist circumference where possible (an individual should be referred to a dietitian if they have comorbidities such as diabetes, heart disease or a BMI of 35 or above)
For women of reproductive age, a urine pregnancy test should be carried out prior to starting valproate (see Section 3, Congenital malformations and developmental disorders)
(see Section 3, Congenital malformations and development disorders)
Side effect baseline (using the VSERS monitoring tool, Appendix 6) 2.2 On-going valproate monitoring 2.2.1 Valproate Summary of Product Characteristics (SPC) recommend frequent
monitoring of LFTs during the first 6 months of therapy, particularly for those at most risk (e.g. young children <3 years) or those with a prior history of liver disease. As with most antiepileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also often transient. In any event weight/BMI, LFTs and FBCs (plus bleeding time and coagulation tests) should be repeated annually
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2.2.3 Amongst usual investigations, tests which reflect protein synthesis, particularly
prothrombin rate, are most relevant. Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of Valproate therapy.
2.2.4 Following each valproate review, it is good practice to make an entry in the progress
notes stating that the appropriate RIO documents have been updated. 2.2.5 There should be regular (for example at CPA review) monitoring of family planning
including the use of contraception and plans to conceive a pregnancy. 2.3 Therapeutic Drug Monitoring of Valproate levels 2.3.1 The pharmacokinetics of Valproate is complex, following a three compartment
model and showing protein-binding saturation. Plasma level monitoring is considered of little use, other than where there is evidence of ineffectiveness, confirming adherence to therapy or concerns about dose-related side-effects. Further guidance is available from pharmacy.
2.4 Side-effect monitoring 2.4.1 Patients should be asked if they are experiencing any side effects related to
Valproate at each appointment. A formal assessment of side effects should be carried out annually. The Valproate Side Effect Rating Scale (VSERS) check list may be used for this purpose (Appendix 6).
2.4.2 Patients/carers should be aware of those symptoms that may indicate serious liver
damage and should be advised to seek immediate medical attention if they develop. The following may precede jaundice:
Non-specific symptoms, usually of sudden onset, such as:
o Asthenia (abnormal physical weakness or lack of strength) o malaise o anorexia o lethargy (lack of energy or vigour) o oedema o drowsiness o Patients experiencing nausea, vomiting or acute abdominal pain should
have a prompt medical evaluation (including measurement of serum amylase) to exclude pancreatitis.
In patients with epilepsy; recurrence of seizures
2.5 Drug-drug interactions 2.5.1 Prescribers must have a system for checking, identifying and acting on any
concurrent medications that may interact with Valproate. It is good practice to check
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the BNF for interaction potential when a new medicine is commenced for a patient stabilised on valproate.
2.5.2 Valproate may potentiate the effect of other psychotropics such as antipsychotics,
monoamine oxidase inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of other psychotropics should be adjusted when appropriate.
2.5.3 In particular, a clinical study has suggested that adding olanzapine to valproate therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence. The two drugs may also have an additive detrimental effect on LFTs.
2.5.4 Prescribers should also be aware of Valproate’s interaction with other
anticonvulsants (particularly carbamazepine and lamotrigine) and smoking. Further guidance on the effects of smoking can be found in HWB-PGN-02.1, Smoking cessation and psychotropic and other drug interactions (excluding clozapine).
2.6 Valproate shared care guidelines 2.6.1 The shared care status of valproate is ‘green’ in all NTW localities. ‘Green’ drugs
are appropriate for prescribing by GPs 3 Congenital malformations and development disorders 3.1 In utero exposure to valproate is associated with serious adverse effects for the
developing child, including:
Congenital malformations. Affecting approximately 10% of cases, these include; neural tube defects (spina bifida, anencephaly), facial dysmorphia and cardiac malformations.
Developmental disorders. Affecting approximately 30-40% of cases, these can include an increased risk of autistic spectrum disorder (approximately three-fold increase in risk), childhood autism (approximately five-fold increase in risk) and delays in early development. There is evidence that children exposed to Valproate in utero will go on to have a lower IQ than children exposed to other antiepileptic drugs.
3.2 The MHRA issued a Drug Safety Update in February 2016; Valproate and risk of
abnormal pregnancy outcomes: new communication materials, stating that:
Valproate should not be prescribed for female children, female adolescents, women of childbearing potential or pregnant women unless other treatments are ineffective or not tolerated.
Female patients and their carers should be counselled about the risk of taking valproate during pregnancy.
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For females planning to become pregnant, all efforts should be made to switch to an appropriate alternative treatment prior to conception.
Valproate treatment must be started and supervised by a doctor experienced in managing epilepsy or bipolar disorder.
3.3 The Drug Safety Update also stipulated communication materials which the MHRA
have asked healthcare professionals to use when valproate is prescribed for females with childbearing potential. These communication materials may be found on the Prescribing and Medicines Management intranet site and at Appendix 1-5 of this document.
3.4 More recently the MHRA have issued a further Patient Safety Alert in April 2017.
Organisations are required to undertake systematic identification of girls and women who are taking valproate, and ensure the MHRA resources are used to support them to make informed choices.
3.5 Prescriber checklist
When valproate is prescribed for any female patient between the age of 8 and 55 years, the Valproate in women of childbearing potential: Prescribers Checklist (Appendix 1) must be completed. The checklist should be completed for those patients newly started on valproate and those who have already been stabilised on the drug.
For female patients outside the range of 8 to 55 years old, prescribers should use their own professional judgement about whether or not the checklist is required.
The completed checklist must be scanned and uploaded to the patient’s medical record as per guidance in RM-PGN-02 Records Management
The Prescribers Checklist (Appendix1) combines the MHRA’s checklist requirements along with NTW-specific requirements.
When Valproate is prescribed for a female patient of childbearing potential, it is the responsibility of the prescriber to ensure she is provided with a Valproate Patient’s Card (Appendix 5), unless she confirms that she already has one. The prescriber must encourage the patient to read the card and enter her name and current date in the spaces provided.
3.5.1 Risk assessment
Prescribers must read the Valproate information booklet for healthcare professionals (Healthcare Professional’s Booklet) (Appendix 2).
Prescribers must always carefully balance the benefits of valproate treatment against the risks. Valproate should only be used when other treatment options have been ineffective or have not been tolerated.
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3.5.2 Capacity assessment
Prescribers must ensure that the patient’s capacity to consent to treatment has been assessed and has been documented in their medical record (NTW(C)05 Consent to Examination or Treatment Policy).
Specific guidance in relation to children, young people, adults who lack capacity and Best Interest decision making can be found in NTW(C)05 Consent to Examination or Treatment Policy.
3.5.3 Information provision
It is the responsibility of the prescriber to ensure that the patient is provided with all necessary information about the risk posed by valproate use during pregnancy. The MHRA recommend that this includes understanding the 30–40% risk of neurodevelopmental disorders and 10% risk of birth defects.
Prescribers must ensure that the patient has been provided with a copy of the Valproate information booklet for patients (Patient’s Guide) (Appendix 3).
Prescribers must ensure that the patient has been informed about the need for effective contraception and has been given information about contraception methods (see 3.5.6).
The above information should be repeated at regular intervals, for example CPA reviews.
Prescribers must ensure that the patient has been informed to promptly contact them if she is planning a pregnancy or becomes pregnant.
3.5.4 Obtaining consent
Prescribers should document capacity to consent to treatment with Valproate, specifically in women of reproductive age taking into account the potential risks in pregnancy.
Where appropriate, prescribers should ask the patient to complete the, Valproate in women of childbearing potential: Patient Consent Form (Appendix 4).
The completed consent form must be scanned and uploaded to the patient’s medical record as per guidance in RM-PGN-02 Records Management
3.5.5 Risk reduction strategies
Prescribers must ensure that a patient has had a negative pregnancy test prior to starting valproate and must advise patients on the need for effective contraception.
Prescribers must ensure that the patient is prescribed folic acid.
3.5.6 Effective contraception
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Prescribers must discuss the following topics with patients and relevant family members/care-givers:
o Assess the most appropriate timing to provide advice on effective contraception methods and refer your patient to a specialist if needed.
o Discuss the most effective method of contraception that best suits the patient’s individual needs and lifestyle, so making it more likely that they will use contraception and use it effectively.
o Consider NICE Guidance recommending long-acting contraception (which is
of particular benefit where the risks of an unplanned pregnancy are high).
o Ensure your patient understands the importance of using contraception to avoid unplanned pregnancy
o Advise your patient to contact you immediately if she thinks she might be
pregnant or becomes pregnant.
Further guidance on the full range of effective contraceptive methods to be offered can be obtained from NICE (Public Health guideline PH51: Contraceptives services for under 25s) and the Faculty of Sexual and Reproductive Healthcare guidelines (https://www.fsrh.org/standards-and-guidance/current-clinical-guidance/).
Although specific data are limited, drug-drug interactions between valproate and contraceptive hormones are unlikely to result in any significant reduction in efficacy of the combined hormonal contraceptive (Baxter, 2017). However, valproate is metabolised by glucuronide conjugation, and therefore its levels may be reduced due to induction of glucuronosyltransferases by ethinylestradiol. (Baxter, 2017; FSRH, 2017)
3.6 Patients who refuse information
Occasionally patients may not wish to receive information when Valproate is prescribed, or they may not currently be receptive to such information. In these circumstances, serious consideration should be given to delaying Valproate treatment until the patient is willing and able to accept information about the risks posed by the drug.
However, if the initiation of valproate is considered to be absolutely necessary, then the prescriber must complete the following actions:
o Complete as much of the Valproate in women of childbearing potential:
Prescribers Checklist (Appendix 1) as possible at the current time, and add this to the patient’s medical record.
o Use the ‘Additional comments’ section of the checklist to make a note of the
information that the patient is currently refusing.
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o Ensure that another attempt to provide the information to the patient is made at the earliest possible opportunity.
o Make an entry in the patient’s medical record stating why it was not possible to
complete the full checklist, and why it was considered necessary to prescribe the medication despite this.
3.7 Sharing information
A copy of the completed Prescribers Checklist (Appendix 1) and Patient Consent Form (Appendix 4) should be forwarded to the patient’s GP along with their discharge summary or clinic letter.
The GP should be asked to remind the patient about Valproate’s adverse effects at every consultation in which medication is discussed.
3.8 Monitoring and follow-up
At all routine treatment reviews, prescribers must ensure that the benefits of valproate continue to outweigh the risks.
For inpatients, the Valproate in women of childbearing potential: Prescribers Checklist (Appendix 1) must be completed when
Valproate is first prescribed and for any newly admitted patients who take the medication. The risks should be reemphasised to the patient when they first go on leave, and when they are discharged.
For outpatients, the Prescribers Checklist (Appendix 1) must be completed when valproate is first prescribed and then at least once every 6 months.
Suspected adverse drug reactions of Valproate should be reported via the Yellow Card reporting scheme (www.yellowcard.mhra.gov.uk).
4 Dispensing valproate
4.1 When Valproate is dispensed by an NTW pharmacy for a female patient of
childbearing potential, it is the responsibility of pharmacy staff to ensure she is provided with a Valproate Patient’s Card (Appendix 5), unless she confirms that she already has one.
4.2 Pharmacy staff must encourage the patient to read the card and enter her name
and current date in the spaces provided.
4.3 If the medication is ‘packed down’ from original containers during the dispensing process, the pharmacy will ensure that the following warning is added to the regular dispensing label:
‘Warning for women and girls: this medicines can seriously harm an unborn baby, always use effective contraception during treatment, if you are thinking
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about becoming pregnant, or you become pregnant, talk to your doctor straight away.’
5 Further information 5.1 Further information can be accessed online via the MHRA’s Drug safety update;
Valproate and of risk of abnormal pregnancy outcomes: new communication materials.
The Drug Safety Update also includes links to printable versions of the communication materials mentioned in this document:
Valproate information booklet for healthcare professionals
Valproate information booklet for patients
Valproate patient card
Hard copies of these materials can be ordered by contacting the Sanofi Medical Information Department on 0845 372 7101, or via e-mail [email protected]
More detailed information about valproate can be obtained by consulting the most recent Summary of Product Characteristics (SPC), available online through the eMC website.
6 References
Joint Formulary Committee. British National Formulary. [Online]. Available at <http://www.medicinescomplete.com/> [Accessed 07/03/2017].
Baxter K (ed), Stockley’s Drug Interactions. 2017. [Online] London: Pharmaceutical Press. Available at <http://www.medicinescomplete.com/> (Accessed 07/03/2017].
Medicines and Healthcare products Regulatory Agency (MHRA). Drug Safety Update volume 9 issue 6 February 2016 [Online]. Available at https://www.gov.uk/drug-safety-update/valproate-and-of-risk-of-abnormal-pregnancy-outcomes-new-communication-materials [Accessed 07/03/2017)
Medicines and Healthcare products Regulatory Agency (MHRA) and NHS Improvement. Patient Safety Alert: Resources to support the safety of girls and women who are being treated with valproate (NHS/PSA/RE/2017/002) [Online]. Available at: https://improvement.nhs.uk/uploads/documents/Patient_Safety_Alert_-_Resources_to_support_safe_use_of_valproate.pdf
Summary of Product Characteristics (SPC) various [Online]. Available at: http://www.medicines.org.uk/ [Accessed on 07/03/2017]
National Institute for Health and Care Excellence (NICE) Bipolar disorder: assessment and management: Clinical guideline [CG185]. 2014. [Online] Available at https://www.nice.org.uk/guidance/cg185 [Accessed 07/03/2017]
9 Northumberland, Tyne and Wear NHS Foundation Trust PPT–PGN–25- Safe Prescribing of Valproate V01-Iss1-Jul 17 Part of NTW(C)38 Pharmacological Therapy Policy
East London NHS Foundation Trust, Medicines Committee 2016. Protocol for using valproate in women of childbearing potential (version 3.0). Supplied by Jennifer Melville, Chief Pharmacist. [Unpublished]
The Faculty of Sexual and Reproductive Healthcare (FSRH). Clinical Guidance: Drug Interactions with Hormonal Contraception. January 2017. [Online] Available at: https://www.fsrh.org/standards-and-guidance/current-clinical-guidance/drug-interactions/ [Accessed 26/04/2017]
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Appendix 1: Valproate in women of childbearing potential: Prescribers Checklist
are This form MUST be completed for ALL female patients who are being treated with valproate for a mental health condition who are aged 8-55 years (clinicians should use their own discretion
outside this range).
ir own discretion outside this range). Patient name:
RiO number:
D.o.B:
I confirm that the above named patient has not responded adequately to, or cannot tolerate, other treatments and so requires treatment with valproate
Capacity assessment
I confirm that I have assessed the above named patient’s capacity to consent to treatment with sodium valproate, and that one of the following statements applies:
(Tick) The patient has capacity to make a decision about the proposed treatment ☐
The patient does not have capacity to consent because of an inability to: Understand information about the decision to be made Retain that information in their mind Weigh that information as part of the decision process Communicate their decision in any way
☐ ☐ ☐ ☐
Information provision I confirm that I have discussed the following points with the above named patient:
(Tick) The approximate 10% chance of birth defects and up to 30-40% chance of a wide range of early developmental problems in children exposed to treatment with valproate during pregnancy
☐
That the risk can be minimised by using the lowest possible effective dose
☐
The need for contraception
☐
The need for regular review of treatment
☐
The need for urgent review if the patient is planning a pregnancy
☐
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Further actions I confirm that I have performed the following actions in relation to the above named patient:
(Tick) Obtained a completed Patient Consent Form (Appendix 4) from the patient, and uploaded this to RiO
☐
Given the patient a copy of the Patient’s Guide (Appendix 3)
☐
Performed a pregnancy test for the patient
☐
Prescribed folic acid for the patient
☐
Made an entry in the patient’s progress notes indicating that I have addressed the discussion points above and assessed their capacity to consent to treatment with valproate
☐
Provide the patient with a Valproate Patient’s Card (Appendix 5), unless she confirms that she already has one and encourage the patient to read the card and enter her name and current date in the spaces provided.
☐
Additional comments Prescriber’s name
Prescriber’s signature
Date
Upload completed form on RiO under ‘Clinical Documentation’ as per guidance in RM-PGN-
02 Records Management
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Appendix 2: Valproate information booklet for healthcare professionals (Healthcare Professional’s Booklet) Available on Prescribing and Medicines Management intranet site (http://nww1.ntw.nhs.uk/services/?id=6288&p=2780)
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Appendix 3: Valproate information booklet for patients (Patient’s Guide) Available on Prescribing and Medicines Management intranet site (http://nww1.ntw.nhs.uk/services/?id=6288&p=2780)
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Appendix 4: Valproate in women of childbearing potential: Patient Consent Form
I understand the following in relation to my proposed treatment with valproate:
(Tick)
Why treatment with Valproate rather than another medicine is considered necessary for me
☐
The risks of an approximately 10% chance of birth defects and up to 30-40% chance of a wide range of developmental problems that can lead to significant learning difficulties in children exposed to treatment with valproate during pregnancy.
☐
That I am advised to use contraception if not planning a pregnancy
☐
That my treatment should be reviewed regularly
☐
That I should request an urgent review if planning a pregnancy PRIOR to attempting to conceive
☐
I confirm that: (Tick)
Doctor ___________________ [insert doctor’s name] has explained the benefits and possible side-effects, including the risks to an unborn baby, of using valproate and I have understood the explanation and the need for effective contraception and folic acid during treatment.
☐
I consent to being treated with Valproate
☐
Patient’s name
Patient’s signature
Date
Prescriber’s name
Prescriber’s signature
Date
Upload completed form on RiO under ‘Clinical Documentation’ as per guidance in RM-PGN-02 Records Management
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Appendix 5: Valproate Patient’s Card
Available on Prescribing and Medicines Management intranet site (http://nww1.ntw.nhs.uk/services/?id=6288&p=2780)
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Appendix 6: Valproate Side Effect Rating Scale (VSERS)
