Consultation outcome

Hana public consultation document

Updated 8 July 2021

In this document there is:

• a summary of the proposed change and the background
• a copy of the proposed patient information leaflet, label and Pharmacy Supply Aid Checklist if the change goes ahead
• a form for your response

The full name of the medicine is `Hana 75 microgram film-coated tablets’ – in this document, we will call it ‘Hana’

Contents:

1. Background about deciding where medicines are available
2. About Hana
3. Proposal to make Hana available as a Pharmacy (P) medicine
4. How the proposal for Hana being available as a Pharmacy (P) medicine was assessed
5. Further details on the application
6. Consultation with stakeholders
7. Advice from the Commission on Human Medicines
8. Summary
9. Tell us what you think

Product details:

Product name: Hana 75 microgram film-coated tablets

Active substance: Desogestrel (DSG)

Licence holder: Laboratoire HRA Pharma

Route of sale/supply: Current: prescription (POM); Proposed: from pharmacies

Indication: Oral contraception in women of childbearing age.

Marketing Authorisation Number: PL 17836/0015

Consultation is open from: 12 February 2021 – 5 March 2021

Reference: ARM 99

Contact: reclassification@mhra.gov.uk

1. Background on deciding where medicines are available

The role of MHRA

MHRA regulates medicines and medical devices in the UK, on behalf of the UK Licensing Authority. This means that MHRA decides whether medicines are available:

• on prescription only - ‘prescription only medicine’ (POM)
• bought from pharmacies - ‘pharmacy medicine’ (P)
• bought from other shops - ‘general sales list medicine’ (GSL)

Re-classification of a medicine

Making a change on where a medicine is available is called ‘reclassification’. This is sometimes referred to as ‘switching’. To decide on this change, MHRA may:

• take advice from its committees of external experts
• take advice from a group (‘stakeholder group’) of health professionals and representatives of people affected by the classification change
• run a public consultation

When a medicine is reclassified, it is usual for reclassification from POM to P to occur in the first instance, and once some experience is gained with the product in the pharmacy (P) setting, further reclassification from P to GSL may occur. In some cases, a medicine may be reclassified directly from POM to GSL, where it meets the necessary requirements and it is safe to do so. To be reclassified directly from POM to GSL, a medicine must meet both the requirements of POM to P and P to GSL reclassification.

To be reclassified from POM to P a medicine must:

• be unlikely to be a direct or indirect danger to human health when used without the supervision of a doctor, even if used correctly
• be generally used correctly (ie not frequently or to a wide extent used incorrectly)
• not contain substances or preparations of substances where the activity of the product or its side effects require further investigation
• not normally be prescribed by a doctor for injection (parenteral administration)

To be reclassified from P to GSL, it must be demonstrated that the medicine may be supplied with reasonable safety in outlets other than in pharmacies. ‘Reasonable safety’ is defined as ‘Where the hazard to health, risk of misuse and need for special precautions in handling of the medicine are small, and where the wider sale would be a convenience to the purchaser’.

Evidence required

A company or organisation can ask MHRA for a medicine to be available as a pharmacy medicine or a general sale medicine. To do this, they need to get together evidence to show that the medicine

a) is likely to be used appropriately, and b) with relatively little danger to the public

This evidence needs to focus on the risk to the public. This includes evidence on the possible abuse or misuse of the medicine. The evidence may include:

• clinical studies
• evidence showing acceptable level of side effects
• advice of experts
• views of relevant health professionals and their professional bodies
• views of relevant public associations and individuals with an interest in the medicine under consideration

How a final decision is made

The final decision on whether to approve a change is made by the MHRA, on behalf of the UK Licensing Authority.

2. About Hana

Hana tablets are an oral contraceptive used for the prevention of pregnancy in women of childbearing age. Hana tablets contain desogestrel (DSG). DSG is a progestogen-only oral contraceptive (also known as a POP or mini-pill) which works in two ways.

Firstly, it changes the consistency of the mucous produced by the cervix, making it more difficult for sperm to travel up into the cervix and beyond.

Secondly, unlike other POPs, it stops women from ovulating (producing an egg from the ovaries). These two actions make DSG a very effective contraceptive.

The DSG POP is monophasic, meaning each tablet contains the same amount of the active ingredient (75microgram DSG). One tablet is taken at the same time every day without a pill-free interval (break for a withdrawal bleed). The efficacy of DSG may be reduced if a dose is delayed by over 12 hours. This missed pill window is significantly longer than for traditional POPs where a delay of only 3 hours can reduce efficacy.

An advantage of DSG is that it may be used by women who are unable to tolerate oestrogens and by women who are breast feeding.

The Commission on Human Medicines (CHM) has advised that this product can be made available from pharmacies as a Pharmacy (P) medicine. This report outlines the background to this decision. Please tell us your views by using the response form at the end of this document (Annex 1). The deadline for comments is 5 March 2021.

The patient information leaflet, label and summary of product characteristics are provided in Annex 2, Annex 3 and Annex 4. The Pharmacy Supply Aid Checklist is provided in Annex 5.

This is the first time an application has been made for an oral contraceptive product to be available as a Pharmacy (P) medicine.

This report relates specifically to the proposal to reclassify Hana from prescription only to a pharmacy medicine.

Medicines containing DSG will still also be available to obtain on prescription from GPs and sexual health clinics.

Information about Hana

Hana contains 75 microgram of desogestrel in each tablet. Hana is a progestogen-only oral contraceptive, also known as a POP or mini-pill. Hana is `monophasic’ since each tablet contains the same amount of active ingredient.

How Hana is used

Hana is as an oral contraceptive used to prevent pregnancy in women of childbearing age.

3. Proposal to make Hana available as a Pharmacy (P) medicine

Proposal applicant

The applicant proposing to make Hana available from pharmacies is Laboratoire HRA Pharma.

The view of the Commission on Human Medicines

The Commission on Human Medicines has advised that Hana can be available as a Pharmacy medicine. Views on the use of this medicine as an oral contraceptive in women of childbearing age were also sought at a meeting of the Medicines for Women’s Health Expert Advisory Group (MWHEAG). The views of the MWHEAG were summarised and provided for CHM when they considered the reclassification application.

Proposed terms of reclassification

Details of the proposed change The application proposes to make Hana available from pharmacies as follows:

• For oral use
• Strength: 75 microgram DSG
• For oral contraception in women of childbearing age
• Dose: one 75 microgram tablet to be taken every day at the same time without a break between packs
• Maximum dose: 75 micrograms
• Maximum daily dose: 75 micrograms
• Maximum quantity of supply: 3 months (3 x 28) at initial consultation 12 months (12 x 28) at repeat supply Women under 18 years of age limited to 3 months (3 x 28)

4. How the proposal for Hana being available as a Pharmacy (P) medicine was assessed

A medicine will be non-prescription unless it fulfils the criteria for prescription control (POM criteria) as set out below. Prescription-only medicine status is required if any of the following apply:

1. A direct or indirect danger exists to human health, even when used correctly, if used without medical supervision

2. There is frequently incorrect use which could lead to direct or indirect danger to human health

3. Further investigation of activity and/or side-effects is required

4. The product is normally prescribed for parenteral administration (by injection)

In the UK, these criteria are laid down in the Human Medicines Regulations 2012, regulation 62(3).

The MHRA considered the application against the criteria for prescription control to assess the suitability for pharmacy availability. It was concluded that none of the criteria apply to Hana as all risks can be managed through the product information and pharmacist training.

The company has produced pharmacy training materials consisting of a Pharmacy Training Guide and a Pharmacy Supply Aid Checklist. The checklist can be completed by the woman prior to consultation, and acts as an aide memoire for the pharmacist in determining if the medicine is suitable for supply. The patient will have the patient information leaflet and packaging to refer to, which contain the key safety messages. As part of consultation in the pharmacy, women will be informed of and sign-posted to information on all methods of contraception available, so that they can make an informed choice regarding the method most suitable for them.

The assessment of the application against each POM criterion is provided below.

4.1 POM Criterion 1 – The product is likely to present a direct or indirect danger to human health, even when used correctly, if used without medical supervision

The main criterion that must be considered in the reclassification of Hana to pharmacy status is that it does not present a direct or indirect danger to human health if used, even correctly, without the supervision of a doctor. A direct danger may be present if the product causes adverse reactions that are important because of their seriousness, severity, or frequency. A danger may also be present if the reaction is one for which there is no suitable preventative action such as being able to identify the group of patients who are at risk if they use the product without medical supervision so that they can be excluded from using the pharmacy product. Direct danger may arise from drug interactions with commonly used medicines. For the product to be suitable for pharmacy status the drug interactions would need to be preventable.

4.1.1 Direct danger to human health

Adverse reactions

Contraceptives containing DSG have been licensed in the UK since 1998. DSG is therefore a well-established product, and its safety profile is well known. Like other POPs, DSG can be used by most women irrespective of age, smoking status and many medical conditions, including stable/treated high blood pressure and cardiovascular diseases.

Post-marketing reports of adverse events with DSG are in keeping with those listed in the Summary of Product Characteristics (SmPC). The SmPC is a legal document that is the basis of information for healthcare professionals on how to use a medicine.

The commonest adverse event reported is vaginal bleeding irregularities. These occur as a result of the inhibition ovulation. Without proper counselling, including that this event is likely to improve or resolve over time, women may discontinue treatment and leave themselves vulnerable to unplanned pregnancy.

Serious events with DSG are rare. Current evidence does not show POPs to have the same risk of serious side effects as combined contraceptive pills. However, as the available evidence is still limited, active venous thromboembolism (blood clots commonly in the legs or lungs), breast cancer and liver impairment are all contraindications for DSG.

Adverse events associated with DSG can be managed through the product information [SmPC, patient information leaflet (PIL) and labelling], and the pharmacy training materials.

The product information and the pharmacy training materials provide comprehensive information about all adverse events with DSG, and how women should be screened and counselled.

Adverse reactions and adolescents

The indication for Hana is contraception for women of childbearing age, including adolescents. The safety and efficacy of DSG in adolescents below 18 years have not been established, and the product information states that no data are available.

In clinical practice, oral contraception has been used widely in women in under the age of 18, including under 16, and the benefits of avoiding an unplanned pregnancy clearly outweigh any risks.

From real world use, the adverse events associated with DSG in those under 18 years do not appear to differ from those experienced by women over the age of 18, but extensive data on this is lacking.

In under 18’s, and especially those under 16, it is essential to establish that the girl is not being exploited or abused and that she is ‘Gillick competent’ to consent to contraception. This is set out by the Fraser Guidelines which help determine if a child is competent to consent to contraception or sexual health and treatment without the knowledge of her parent or guardian. In Scotland the Age of Legal Capacity Act applies but the principles are similar. Pharmacists are already familiar with safeguarding and consent, through the provision of emergency contraception services.

The product information for Hana makes it clear that safety and efficacy have not been established for women below 18 years, but the pharmacy training materials show that the benefits are likely to outweigh the risks in most girls. The training and the checklist ensure pharmacists are reminded of how to safely supply contraception to girls under 18, and especially those under 16. Pharmacists are encouraged to provide no more than a 3-month supply of Hana to ensure there is opportunity for girls to be followed up and reassessed in terms of safeguarding and exploitation. There is not anticipated to be increased risk to girls under the age of 18 years through pharmacy supply of DSG.

Drug interactions

There are many drugs that can interact with DSG if they are used at the same time. The effects of these interactions can be as follows:

Drugs which reduce the efficacy of DSG

Medicines known as enzyme inducers, speed up the metabolism of DSG so that levels of the drug drop below those needed for effective contraception. The effects can last for up to 28 days after an enzyme inducer is stopped. Examples of drugs that can do this include:

Barbiturates, carbamazepine, phenytoin, primidone, rifampicin, and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate, rifabutin and products containing the herbal remedy St. John’s Wort (hypericum perforatum).

If short term use of such medicines is essential during treatment with DSG, then additional barrier methods of contraception are required during use and for 28 days after stopping. If an enzyme inducer is intended to be used long-term, then the woman should discuss her condition and her contraceptive needs with her doctor, as an alternative method of contraception may be more appropriate.

Drugs which increase exposure to DSG

Medicines known as enzyme inhibitors reduce the metabolism of DSG so that it is not removed from the body so quickly and levels might build up beyond the recommended therapeutic range. This could result in an increase in adverse events. Drugs with the potential to do this include:

Strong CYP3A4 enzyme inhibitors (e.g. ketoconazole, itraconazole, clarithromycin) and moderate CYP3A4 enzyme inhibitors (e.g. fluconazole, diltiazem, erythromycin)

Drugs with variable effects on serum DSG levels (reducing or increasing)

Some medicines have the potential to increase or decrease DSG levels, so individual prescribing information should be referred to, and an additional barrier method of contraception may be required. Examples include: HIV protease inhibitors (e.g. ritonavir, nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine) and/or combinations with Hepatitis C virus (HCV) medicinal products (e.g. boceprevir, telaprevir).

Interactions with emergency hormonal contraception

DSG can inhibit the ability of the emergency contraceptive pill containing ulipristal acetate to delay ovulation and prevent an unplanned pregnancy. Conversely, ulipristal acetate can reduce the effect of DSG as it binds strongly to the progesterone receptor. Concomitant use should be avoided. DSG should be started/restarted no sooner than 5 days after emergency contraception with ulipristal acetate.

Effect of DSG on other drugs

Hormonal contraceptives may interfere with the metabolism of other drugs. For example, ciclosporin levels may increase and lamotrigine levels may decrease. All drug interactions with Hana can be managed through the product information [SmPC, patient information leaflet (PIL) and labelling] and pharmacy training materials.

Pharmacists will already be familiar with these interactions. The product information has been strengthened with regard to drug interactions to ensure the information is comprehensive. The pharmacy training materials and check list make it clear that pharmacists should check ALL medication (including over the counter and herbal products) a woman is taking for interactions with DSG. Clinically relevant interactions will necessitate referral to a doctor for discussion of contraceptive options. Pharmacists are encouraged in the training to counsel women on the importance of informing other healthcare professionals that they are taking DSG.

Minimising direct risks

The risk from adverse drug reactions and interactions can be adequately managed through the supply model, the product information and the pharmacy training materials. Pharmacists are skilled professionals already practised in medicines management including advising on adverse events and interactions. The product information, pharmacy training materials and pharmacist checklist, ensure they have all relevant information on the important adverse events and interactions for DSG. This will allow pharmacists to identify women suitable for supply and be able to counsel those women appropriately.

The MHRA considers that the direct risks can be minimised to an acceptable level for pharmacy supply of Hana.

4.1.2 Indirect danger to human health

Medicines may present indirect dangers if their side effects mimic the symptoms of other conditions, leading to those conditions being masked or dismissed. Alternatively, indirect dangers may occur if unsuitable patients are supplied with the product or if pharmacy supply results in care that is inferior to patients receiving a prescription. Indirect dangers can also refer to the danger to a foetus from exposure to medicines.

The following potential indirect dangers have been identified for pharmacy supply of Hana.

Masking of underlying conditions

Underlying conditions may be masked by DSG if symptoms from the condition are mistaken for adverse events of Hana. Examples where this may occur are:

Gynaecological malignancies (cancers)

Malignancies of the female reproductive tract can present with vaginal bleeding. Given that DSG commonly causes irregular vaginal bleeding, it is essential that any undiagnosed bleeding is investigated prior to starting Hana. It is also important that any vaginal bleeding outside of that expected to occur with DSG, is referred for further investigation. For example, post-coital bleeding (bleeding after sex), is not typical for DSG and may be a sign of cervical cancer or a sexually transmitted infection (STI). The SmPC and PIL states that undiagnosed vaginal bleeding is a contraindication to Hana use. The pharmacy training materials provide detailed information and guidance on vaginal bleeding and when to refer to a doctor.

Sexually transmitted infections

STI’s can present with irregular bleeding and this may be missed if the symptom is put down to Hana. Untreated STI’s can result in infertility. Counselling about sexual health should automatically occur as part of contraceptive counselling, including reminders that only barrier methods of contraception protect against STIs. Any woman with symptoms of an STI or at potential risk, should be referred to sexual health services. A reminder about sexual health is included in the SmPC and PIL and further information and guidance is included in the pharmacy training materials. Pharmacists are already experienced in counselling on sexual health given that they provide chlamydia screening.

Ectopic pregnancy

The risk of ectopic pregnancy with Hana is very low because it inhibits ovulation. However, if a woman was to suffer an ectopic pregnancy whilst taking DSG, vaginal bleeding may be mistakenly put down to the medicine and the ectopic pregnancy missed. Failure to detect an ectopic pregnancy in good time, can be fatal or result in loss of fertility. Typical symptoms and signs of an ectopic pregnancy are highlighted in the SmPC and PIL, and the situation is discussed further in the pharmacy training materials.

The product information and pharmacy training materials are adequate to minimise the risk of masking underlying conditions.

Use by contraindicated women

The contraindications listed for Hana in section 4.3 of the SmPC are:

• active venous thromboembolic disorder (VTE)
• presence or history of severe hepatic disease as long as liver function values have not returned to normal
• known or suspected sex-steroid sensitive malignancies
• undiagnosed vaginal bleeding
• hypersensitivity to the active substance or to any of the excipients

Venous thromboembolism (VTE - blood clots commonly in legs or lungs)

The SmPC, PIL and pharmacy training materials clearly state and discuss this risk, including how to identify the condition. They advise that Hana cannot be used in the case of active VTE but can be used in women with past history of VTE, provided they are counselled about the risk of recurrence. As an association between DSG and VTE has not been established, the risk of inadvertently supplying Hana to a woman with VTE is likely to be low.

Presence or history of severe hepatic disease

The SmPC, PIL and pharmacy training materials make it clear that Hana is contraindicated in women with a history of severe hepatic disease, as long as liver function values have not returned to normal. As pharmacists are unlikely to have access to liver function test results, pharmacy training materials recommend all women with past or active liver disease are referred to their doctor for consideration of the suitability of Hana.

Known or suspected sex steroid dependent malignancy

Sex steroid dependent malignancies (e.g. breast cancer and endometrial cancer), may be worsened by treatments containing hormones. For this reason, the SmPC, PIL and pharmacy training materials state this contraindication and offer further advice on breast cancer. Although breast cancer is known to be associated with combined contraceptive pills, the available evidence does not currently support a link with POPs. However, the evidence is limited, and an association has not been excluded. Any association is likely to be of a similar magnitude to combined pills. Pharmacists are encouraged to not supply to any woman with a personal history of breast cancer or other sex steroid dependent malignancy. Inadvertent supply to a woman with a sex steroid dependent malignancy is likely to be low risk.

Undiagnosed vaginal bleeding

This has already been considered above and can be well managed by pharmacists supported by the product information and pharmacy training materials.

Hypersensitivity to the active substance or excipients

Pharmacists are well practised in checking the suitability of medicines and will be experienced in asking about allergies. The SmPC, PIL and pharmacy training materials for Hana, highlight possible allergens and remind pharmacists to check the list of ingredients and excipients in women with known allergies.

The product information and pharmacy training materials clearly highlight contraindicated conditions including how to recognise them and how to proceed when they are present. These documents are considered to adequately reduce the risk of supply to contraindicated women. The risk of supply to a woman with an undetected contraindicated condition is generally considered low.

Unrecognised early pregnancy with consequent foetal exposure to DSG

Available evidence suggests that foetal exposure to normal doses of contraceptive hormones has no adverse impact on pregnancy outcomes or risk of foetal abnormality. However, given that evidence is limited, Hana should not be used in pregnancy.

Pharmacists are encouraged in the SmPC and pharmacy training materials to reasonably exclude pregnancy prior to every supply of Hana. This is done by asking the woman questions about her periods, sexual activity and pregnancy history. The applicant has developed a pregnancy exclusion tool, based on the criteria for reasonably excluding pregnancy drawn up by the Faculty of Sexual and Reproductive Health (FSRH). The tool is included in the Pharmacy Training Guide and referred to in the Pharmacy Supply Aid Checklist.

Pharmacists are advised to tell women to start taking Hana on the first day of their menstrual period. This will also help ensure she is not pregnant.

A foetus may be exposed to DSG if:

The woman is already pregnant when she starts Hana

The criteria to exclude pregnancy should pick up most pregnancies or potential pregnancies prior to supply. However, it is always possible that a pregnancy is not detected. A pregnancy test is not reliable until at least 3 weeks following the last episode of unprotected sexual intercourse. Starting Hana on day 1 of the cycle will help ensure a woman is not pregnant.

Quick starting

Sometimes it may be considered necessary to start Hana immediately without waiting for the first day of the menstrual cycle. This is known as quick starting and may be considered necessary if a woman is especially vulnerable to the risk of unplanned pregnancy if regular contraception is not started straight away. In this situation, it may not be possible to exclude pregnancy prior to starting, and a foetus may therefore be exposed to DSG.

Quick starting is outside of the product licence (off label use). The pharmacy training materials include information and signposting to guidance on quick starting, to ensure pharmacists are fully aware of the practice. It is however made clear that this is off label use.

Hana fails to prevent pregnancy

All contraceptive pills have an inherent failure rate. In normal use the typical failure rate of oral contraceptives is 9%. Oral contraception may fail if efficacy is reduced by missed pills or interacting medicines. As DSG has a side effect of amenorrhoea (cessation of menstrual periods), women taking Hana may not realise they are pregnant until some of the later symptoms of pregnancy develop. The SmPC, PIL and pharmacy training materials clearly outline how Hana should be taken, including management of missed pills and the dangers from interacting medicines. Using the pregnancy exclusion criteria before every supply, will help ensure pregnancies are detected as soon as possible and reduce the potential for foetal exposure to Hana.

The product information and pharmacy training materials adequately minimise the potential of inadvertent foetal exposure, and the risk if this should occur is considered to be low.

Risk of worsened outcomes as a result of pharmacy supply

Concerns may be raised that supply in the pharmacy without contact with the usual health care professionals involved in sexual health, might result in missed opportunities for health promotion and protection.

Sexually transmitted infections

This has been discussed above. Pharmacists are already experienced in sexual health counselling through provision of chlamydia screening. Product information and the pharmacy training materials remind pharmacists of the importance of discussing sexual health with women, and the fact that only barrier methods protect against STI’s. Pharmacists are encouraged to refer women to sexual health services if they have or are at risk of an STI.

Supply of Hana by a pharmacist will therefore not jeopardise sexual health or put women at increased risk of STIs.

Possible sub-optimal choice of contraception

The fact that Hana is available from a pharmacy without prescription may encourage women to opt for this product when a different contraceptive may be more appropriate for them. The pharmacy training materials encourage pharmacists to discuss all methods of contraception with a woman before she makes a choice to ensure she is using the method most suitable for her. Therefore, although the only regular contraceptive available from the pharmacy will be DSG, all other methods will be discussed, and women referred on if they would prefer a different method.

The pharmacy training materials ensure the pharmacist conducts a holistic consultation with women requesting contraception, including all elements of sexual health and all available contraceptive methods. Pharmacists already have relevant knowledge and experience to be able to do this. There is nothing to suggest that women supplied with Hana from a pharmacist will have worsened outcomes as a result.

Minimising indirect risks

The indirect risks of masking underlying conditions, inadvertent foetal exposure and worsened health outcomes are all addressed through the supply model, the product information and the pharmacy training materials. Pharmacists already have relevant knowledge and experience to manage many of these risks. Reminders and additional guidance provided in the training and checklist builds on what pharmacists already know and do.

The MHRA considers that the indirect risks can be minimised to an acceptable level for pharmacy supply of Hana.

Overall conclusion on POM Criterion 1 (The product is likely to present a direct or indirect danger to human health, even when used correctly, if used without medical supervision)

POM criterion 1 is not considered to be fulfilled for Hana. Lack of medical supervision is not anticipated to result in direct or indirect danger to human health, provided the advice in the product information, pharmacy training materials and checklist is followed.

4.2 POM Criterion 2 – The product is frequently and to a very wide extent used incorrectly, and as a result is likely to present a direct or indirect danger to human health

The ways that DSG could be used incorrectly are:

• misuse/abuse
• medication errors
• use outside of the intended population/potential off-label use
• overdose

Misuse/abuse

There is no indication from clinical trials, post-marketing experience or scientific literature that there is a real risk of deliberate misuse or abuse of DSG. There are no underlying pharmacological mechanisms or neural or behavioural signs and symptoms, that suggest DSG would induce drug-seeking behaviour.

Medication Errors

Hana is intended to be started on day 1 of the menstrual cycle for immediate contraceptive protection. It can also be started on day 2-5 where additional contraceptive precautions are required for the first 7 days of tablet taking. Starting on any other day of the cycle (Quick starting), may be considered necessary for some women, and requires 7 days of additional contraceptive precautions, but as discussed above, quick starting is outside of the product licence.

Irrespective of which day Hana is started on, tablets are to be taken every day continuously, and a new pack is started immediately after the previous pack without any break for a menstrual bleed.

Pills should be taken at the same time each day, and no later than 12 hours from the time they are due. If a woman is more than 12 hours late, the pill is considered ‘missed’ and contraceptive efficacy may be reduced. Gastrointestinal disturbances can also result in pills essentially being ‘missed’. Additional contraceptive precautions will be required until 7 days of normal pill taking has been achieved. Emergency contraception may also be indicated for missed pills.

Interacting medicines may also threaten the contraceptive efficacy of Hana. (See Direct Risks in POM Criterion 1 above)

Pharmacists already have knowledge and experience in advising women how best to take their contraceptive pills. Their prior knowledge is supplemented by the product information, pharmacy training materials and checklist which provide comprehensive information on how to take Hana and actions to take with ‘missed’ pills and interacting medicines. The patient information leaflet provides the same information to women in lay language, with advice to discuss with the pharmacist if anything is not clear.

The product information, pharmacy training materials and checklist help ensure the risk of medication errors is minimised.

Use outside the intended population/off label use

It is unlikely that Hana will be used outside of its indication of contraception.

One area of off-label use that must be considered is the practice of ‘Quick starting’, which has already been discussed above. ‘Quick starting’ is commonly used in family planning services and involves starting a contraceptive on any day of the cycle instead of waiting for day 1. The benefit is a woman has contraceptive protection sooner, but the risk is that an early pregnancy may be exposed to DSG. Additionally, as DSG can cause amenorrhoea, diagnosis of any pregnancy may be delayed which increases the time that a foetus is exposed and reduces time for antenatal care/consideration of options.

The pharmacy training materials provide information and signposting on quick starting because it is commonly used in clinical practice, and therefore important for pharmacists to be aware. It is made clear that the practice constitutes off-label use, and that if a pharmacist chooses to ‘quick start’ a woman on Hana, they are doing so using their own professional judgement. They are referred to relevant guidance on quick starting and guidance on supplying medicines off-label.

It has already been discussed that the risk to a foetus from exposure to DSG is very low. The consequences of a woman being quick started on Hana off-label are therefore not anticipated to be serious.

Overdose

The risk from overdose of Hana is low. From the evidence provided with use of DSG as a prescription only medicine, there have been no reports of serious deleterious effects from overdose. Symptoms that may occur are nausea and vomiting and in young girls there may be slight vaginal bleeding. Treatment of overdose is symptomatic only.

Pharmacy supply is not expected to be associated with an increased risk of overdose, especially as pharmacists will not be supplying any more tablets than women can already obtain from their doctors. Pharmacists are encouraged to provide a 3-month supply for the initial supply, (and for any supply to a girl under 18). Women over the age of 18 can be given up to 12 months supply once they are established and happy on Hana. This is consistent with general practice and family planning services.

Minimising incorrect use

Abuse, misuse and overdose are not anticipated to be issues with Hana. The biggest risk of incorrect use comes from failure to take the product correctly or failure to take appropriate action if the product has been taken incorrectly. Pharmacists are already trained and experienced in providing advice on all these areas for oral contraceptives. They are further supported by the product information (including the PIL), and the pharmacy training materials and checklist. These contain comprehensive information on how to take Hana and what to do in case of inconsistent or incorrect use.

The risk of off-label use is low. The practice of ‘quick starting’ Hana outside of day 1-5 of the menstrual cycle is common in family planning practice but is off-label use. The pharmacy training materials provide information about the practice so that pharmacists are familiar with it and have relevant information, but it is made clear this is outside of the product licence.

Overall conclusion on POM criterion 2 (The product is frequently and to a very wide extent used incorrectly, and as a result is likely to present a direct or indirect danger to human health.)

The second POM criterion is not considered to be fulfilled for Hana, because the risks of direct or indirect danger to human health from incorrect use, can be adequately managed through the product information and pharmacy training materials.

4.3 POM Criterion 3 – The product contains substances or preparations of substances of which the activity requires, or the side effects require, further investigation

DSG is a well-established product having been widely used as a POP in the UK since 1998. Its efficacy and safety profile are well known, and there are no issues requiring further investigation.

Overall conclusion on POM criterion 3

The 3rd POM criterion is not considered to be fulfilled for Hana.

4.4 POM Criterion 4 – The product is normally prescribed by a doctor for parenteral administration (that is, by injection).

Hana is a tablet intended for oral administration only.

Overall conclusion on POM criterion 4

The 4th POM criterion is not considered to be fulfilled for Hana.

5. Further details on the application

5.1 Risk Management Plan

The application contained a risk management plan (RMP), which documents everything that is known and not known about the safety profile of a product, including any plans for further characterising risks and minimising risks.

The RMP for Hana details the following:

Safety Concerns (Important identified and potential risks)

None of the risks known to be associated with DSG (identified risks), are considered especially serious or important.

Potential risks are those that may be associated with DSG, but available evidence does not currently prove they are linked. The following potential risks of DSG are considered important:

• venous thromboembolism (blood clots in veins, commonly the legs and lungs)
• arterial thromboembolism (blood clots in arteries commonly leading to heart attack and stroke)
• disturbances of liver function
• breast cancer
• benign and Malignant Liver tumours
• drug interactions

Monitoring of the safety concerns

The safety concerns associated with Hana can be monitored through the routine activities that pharmaceutical companies have to undertake legally to monitor their products, (routine pharmacovigilance). No additional monitoring is considered necessary.

Further characterising the safety concerns (Additional pharmacovigilance)

None of the safety concerns are considered to require further investigation or study, either because current knowledge is considered adequate, or because studies are unlikely to provide useful additional information.

Minimising the safety concerns

The risk of all safety concerns and adverse events for Hana are minimised through routine measures including the product information.

The safety concerns for the supply of Hana in the pharmacy will be minimised further through an additional risk minimisation measure of pharmacist training materials and a Pharmacy Supply Aid Checklist. These will highlight the important potential risks of DSG. They will also ensure that pharmacists know how to identify relevant conditions and advise and manage women appropriately.

Measuring the effectiveness of the additional risk minimisation measure of pharmacist training

Following market launch of Hana, the applicant is required to undertake a survey-based study, (post-authorisation safety study or PASS), to assess how effective the pharmacist training materials are at ensuring competence and confidence to supply Hana safely and appropriately. The pharmacist’s views on the training will be sought, as well as a demonstration of understanding of key messages, and the ability to make correct decisions about whether to supply to a woman or not.

5.2 Pharmacy support materials

As already discussed, additional resources in the form of pharmacy training materials will be provided for pharmacists. These are optional and cover the following areas:

Pharmacy Training Guide – The Pharmacy Guide provides information to pharmacists on the safe use of Hana ensuring it is only supplied to suitable women with appropriate counselling and advice. The guide covers initial supply, repeat supply, and switching method of supply, for example from prescription supply by a doctor to purchase in the pharmacy. Women are made aware of information on all methods of contraception available to them, so that they can make an informed choice about which method would be most suitable for them. They are reminded that only barrier methods of contraception protect against STIs, and they are encouraged to attend routine cervical and breast screening (where applicable) and to be breast aware. To ensure continuity of care, women are encouraged to inform their doctor and other healthcare professionals that they have been supplied with Hana from their pharmacy.

Pharmacy Supply Aid Checklist – The checklist acts as an aide memoire and allows the pharmacist to check the suitability of Hana. This covers age of the woman, current or past medical conditions, medicines (or herbal remedies) the woman is taking, criteria for excluding pregnancy and use following emergency hormonal contraception. It also provides a reminder of side effects of DSG and counselling advice to provide to the woman.

The Pharmacy Supply Aid Checklist is provided at Annex 5.

5.3 Label and leaflet

The patient information leaflet and label are provided in Annex 2 and Annex 3.

5.4 Summary of Product Characteristics

The Summary of Product Characteristics is provided in Annex 4. This document is a description of the properties of Hana and the conditions attached to its use. It is used as a reference by healthcare professionals.

6. Consultation with stakeholders

As part of the assessment process MHRA undertook a patient and healthcare professional engagement exercise to inform the CHM decision regarding availability of DSG from pharmacies. This included representation from individual patients, patient groups, pharmacists, GPs, professional bodies (Royal Pharmaceutical Society, FSRH, Royal College of GPs). The exercise explored the access to oral contraceptives, whether patients would welcome wider availability, and the professional views of those currently involved in prescribing this medicine on widening access. There was strong support from all stakeholders for making DSG available to purchase from pharmacies in addition to being available through sexual health clinics and GPs on prescription.

MHRA separately discussed widening access of this medicine with health policy officials in the Devolved Administrations and this also met with strong support.

7. Tell us what you think

• Hana 75 microgram film-coated tablets are an oral contraceptive used to prevent pregnancy in women of childbearing age
• We propose to make it available in pharmacies
• Medicines containing desogestrel will still be available on prescription from GPs and sexual health clinics.
• Women will have choice in where they obtain supply of this medicine from, either on prescription or from pharmacies and may opt to switch between methods of supply
• We consider that this product may be available as a pharmacy medicine
• The Commission on Human Medicines has advised that this product can be available as a Pharmacy (P) medicine
• We want to know what you think about this change

Please tell us your views using the form in Annex 1. The deadline for comments is 5 March 2021.