Patient Group Direction (PGD) for the supply of mefloquine (Lariam®) for the prophylaxis of malaria

1. Clinical condition or situation to which the direction applies

Indication

• Chemoprophylaxis of plasmodium falciparum malaria where there is mefloquine

sensitivity.

Objectives of care

• Malaria prevention in travellers to endemic areas thereby reducing morbidity.

Inclusion criteria

• Valid consent has been obtained from the patient/carer who does not want to consult with their GP and would prefer to access treatment from the PGD user.

• Adults and children weighing 5kg or more, and from 12 months of age, after risk assessment, and evaluation of travel plans, where mefloquine is deemed to be the most appropriate chemoprophylactic agent.

• Risk must be identified with reference to current recognised sources such as:

̵ http://www.travax.nhs.uk/

̵ https://www.fitfortravel.nhs.uk/home

̵ http://travelhealthpro.org.uk/country-information/

Exclusion criteria

(Refer to current and relevant SPC (Great Britain or Northern Ireland), British National Formulary (BNF) and PHE Advisory Committee on Malaria Prevention (ACMP) guidance for additional details)

• Patients for whom no valid consent has been received.

• Hypersensitivity to the active substance(s) or related compounds (e.g. quinine, quinidine) and to any of the excipients or trace residuals in Larium®. See section 2 and

6.1 of the relevant Summary of Product Characteristics (SPC).

• Individuals under 12 months of age.

• Individuals weighing less than 5kg.

• Epileptic or psychiatric disorders, comprising of active depression, a history of depression, generalised anxiety disorder, psychosis, suicide attempts, suicidal ideations and self-endangering behaviour, schizophrenia or other psychiatric disorders, or with a history of convulsions of any origin.

• Those with severe impairment of liver function.

• Breastfeeding individuals.

• Underlying cardiac conduction disturbances.

• Those currently taking halofantrine. Halofantrine must not be used during mefloquine chemoprophylaxis or treatment of malaria or within 15 weeks after the last dose of mefloquine.

• Has a history of blackwater fever (a complication of falciparum malaria with massive intravascular haemolysis causing haemoglobinuria).

• Those with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

• Patients with Myasthenia Gravis.

1. Clinical condition or situation to which the direction applies – continued

Cautions

(including any relevant action to be taken)

Direct oral anticoagulants (DOAC) (1)

• Dabigatran etexilate, rivaroxaban, apixaban and edoxaban are the most commonly available DOAC. Mefloquine inhibits CYP3A4 and p-glycoprotein, so could increase DOAC plasma concentrations which might lead to an increased bleeding tendency. Pregnancy

• Pregnant women should be discouraged from travelling in endemic areas. If travel is unavoidable, mefloquine may be supplied according to current national guidelines (2).

• Mefloquine use in the first trimester must be undertaken with caution but can be used in all trimesters for travellers to high-risk areas. It seems unlikely that mefloquine is associated with adverse foetal outcomes (1).

  Planning a pregnancy

• Women of childbearing potential travelling to malarious areas in which multiple resistant P. falciparum is found and who are receiving mefloquine for the treatment and prophylaxis of malaria should take reliable contraceptive precautions for the entire duration of therapy and for three months after the last dose of mefloquine (4). Psychiatric disturbances

• If psychiatric disturbances occur during prophylactic use (depression, mood changes, insomnia, anxiety, confusion, hallucinations, abnormal dreams/nightmares, panic attacks, restlessness, forgetfulness, psychosis and paranoia, emotional instability, aggression or agitation), mefloquine should be discontinued and medical advice sought

  (2).

  Renal insufficiency

• Due to limited data, mefloquine should be administered with caution in patients with renal impairment (2).

  Eye disorders

• Any patient presenting with a visual disorder should be referred to a physician as certain conditions (such as retinal disorders or optic neuropathy) may require stopping treatment with mefloquine (2).

  Effects on ability to drive or operate machinery

• Caution should be exercised with regard to activities requiring alertness and fine motor coordination such as driving, piloting aircraft, operating machinery and deep-sea diving, as dizziness, vertigo or a loss of balance, or other disorders of the central or peripheral nervous system and psychiatric disorders have been reported during and following the use of mefloquine. These effects may occur after therapy is discontinued due to the long half-life of the drug (2) (4).

  Diving

• Mefloquine lowers the seizure threshold, and its side effects could potentially be confused with decompression or narcosis events. For this reason an alternative anti-

malarial should be considered for diving holidays (3).

1. Clinical condition or situation to which the direction applies – continued

Cautions

(including any relevant action to be taken)

Oral live typhoid vaccines

• When mefloquine is taken concurrently with oral live typhoid vaccines, attenuation of immunisation cannot be excluded. Vaccination with oral attenuated live bacteria should therefore be completed at least 3 days before the first dose of mefloquine (2) (5). Brain injury

• For people who have suffered traumatic brain injury, the decision to recommend mefloquine chemoprophylaxis should be made on an individual basis after a detailed risk assessment (3).

  Pneumonitis

• Pneumonitis of possible allergic etiology has been reported in patients receiving mefloquine. Patients who develop signs of dyspnoea, dry cough or fever etc. while receiving mefloquine should be advised to contact a doctor to undergo medical evaluation (2).

  Neuropathy

• Mefloquine should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (2).

  Immunosuppressed

• Long-term visitors run a higher risk of catching malaria than short term travellers to the same location. Furthermore, once infected, the risk of developing severe or complicated malaria is higher in certain groups, such as the elderly (over 70 years old), the immunosuppressed, those with complex co-morbidities and pregnant women. (1) Other considerations

• Healthcare professionals must not delegate their responsibility and have the right to refuse treatment to eligible patients based on their own clinical judgement.

• Where there is doubt, treatment should not be initiated until the patient has sought

advice from the appropriate healthcare professional.

1. Clinical condition or situation to which the direction applies – continued

Product interactions

• Prior to supply and where indicated, medication that the patient is using should be checked for product interactions using the British National Formulary (BNF) and SPC. This includes checking that the patient’s medication does not suggest conditions that are excluded from treatment under this PGD.

  Halofantrine

• There is evidence that the use of halofantrine during mefloquine chemoprophylaxis or treatment of malaria, or within 15 weeks after the last dose of mefloquine, causes a significant lengthening of the QTc interval. Clinically significant QTc prolongation has not been found with mefloquine alone (2).

  Other drugs that prolong the QTc interval

• Concomitant administration of other drugs known to alter cardiac conduction (e.g. anti-arrhythmic or beta-adrenergic blocking agents, calcium channel blockers, antihistamines or H1-blocking agents, tricyclic antidepressants and phenothiazines) might also contribute to a prolongation of the QTc interval (2).

  Anticonvulsants and drugs lowering the epileptogenic threshold

• Patients taking mefloquine while on concomitant treatment with anticonvulsants (e.g. valproic acid, carbamazepine, phenobarbital or phenytoin) had loss of seizure control and lower than expected anticonvulsants blood level. Therefore, dosage adjustments of anti-seizure medication may be necessary in some cases (2).

• Concomitant administration of mefloquine and drugs known to lower the epileptogenic threshold (antidepressants such as tricyclic or selective serotonin reuptake inhibitors (SSRIs); bupropion; antipsychotics; tramadol; chloroquine or some antibiotics) may increase the risk of convulsions (2).

  Other Interactions/ Inhibitors and Inducers of CYP3A4:

• Mefloquine does not inhibit or induce the cytochrome P450 enzyme system. It is therefore not expected that the metabolism of drugs given concomitantly with mefloquine is affected. However, inducers (rifampicin, carbamazepine, phenytoin, efavirenz) or inhibitors of the isoenzyme CYP3A4 may modify the pharmacokinetics/metabolism of mefloquine, leading to an increase or decrease in mefloquine plasma concentration. The clinical consequences of these effects are unknown, and a close clinical surveillance is warranted (2) (3).

  Interaction with vaccines

• When mefloquine is taken concurrently with oral live typhoid vaccines, attenuation of immunisation cannot be excluded. Vaccinations with oral attenuated live bacteria should therefore be completed at least 3 days before the first dose of mefloquine (2) (3).

• Ritonavir levels are reduced by mefloquine due to decreased absorption (3).

1. Clinical condition or situation to which the direction applies – continued

Action if patient is excluded from the service

• Discuss with patient and document the reasons for exclusion from treatment under the PGD.

• The risk to the individual of not taking chemoprophylaxis must be considered and discussed with the traveller. Document advice given.

• Offer the patient written information on how to avoid mosquito bites and how to recognise the symptoms of malaria infection, based on current guidelines together with general travel health advice.

• If the patient has consented, refer them to their GP and/or inform their GP.

• Signpost to other services if appropriate.

• Document the reasons for exclusion and any action taken, in the patient’s medication

  record.

• When treatment is postponed reschedule as appropriate.

Action if patient declines the service

• Ensure patient/carer fully understands the risks of declining the service.

• Advise the patient/carer about the benefits of the service.

• Refer patient to GP if appropriate.

• Document the reasons for declining the service and any action taken, including advice given to the patient.

• Reschedule treatment if appropriate.

• Offer the patient written information on how to avoid mosquito bites and how to recognise the symptoms of malaria infection, based on current guidelines together with general travel health advice.

2. Description of treatment

Name, strength & formulation of drug

Supplier

Name of

product

Composition

Pharmaceutical form

Excipients

Age indications

Neon Healthcare Ltd

Lariam®

Each tablet contains 250 mg mefloquine (as

274.09 mg

mefloquine hydrochloride). Each tablet contains 50.61 mg of lactose monohydrate.

Tablet. White to off- white cylindrical biplanar tablets, cross scored and imprinted with LA-RI-AM-CP on one face.

• Microcrystalline cellulose

• Lactose

• Crospovidone

• Maize starch

• Ammonium-calcium alginate

• Poloxamer (polyoxyethylene- polyoxypropylene copolymer)

• Talc

• Magnesium stearate

Adults and children weighing 5kg or more, or older than 12 months of age

• For a full list of excipients, see section 2 and 6.1 of the relevant SPC.

Legal status

• POM – Prescription Only Medicine

Dose/dose range

• For malaria prophylaxis the stated dose of Lariam® should be given once weekly, always on the same day (2).

• In order to ensure, before arrival in endemic area, that Lariam® administration is well tolerated, it is recommended to start chemoprophylaxis with Lariam® 10 days before departure (i.e. first intake 10 days before departure and 2nd intake 3 days before departure). Subsequent doses should be taken once a week (on a fixed day) (2).

• Treatment should be continued for 4 weeks after leaving a malarious area (2).

• Dosing should be administered in accordance with the table below (2).

Weight

Dosage

5-19kg

1/4 tablet weekly (62.5mg)

20-30 kg

1/2 tablet weekly (125mg)

31-45kg

3/4 tablet weekly (187.5mg)

Adults and children of more than 45kg

body weight

1 tablet weekly (250mg)

Use of PGD outside terms of SPC

• This PGD covers treatment in England, Scotland, Wales and Northern Ireland. Please note that Northern Ireland may have a separate SPC from Great Britain and guidance may differ. Please refer to the relevant SPC for more information.

• Although healthcare professionals have the right to refuse treatment even where a patient is

eligible, they cannot override PGD exclusions.

Route/method of administration

• The tablets should be swallowed whole, preferably after a meal, with plenty of liquid (2).

• If necessary, the tablets can be crushed and mixed with jam/honey (or similar) just before administration (4).

Frequency of administration

• The stated dose is to be given once weekly, always on the same day. Treatment should be continued for 4 weeks after leaving a malaria endemic area (2).

Quantity to supply

• Supply should be sufficient to cover the treatment period, comprising of pre- and post-travel treatment requirements.

Follow up / minimum or maximum period

• The minimum treatment period is 6 weeks (2).

• The maximum recommended duration of administration of Lariam® is 12 months (2).

• For further information on long term use, refer to ACMP guidelines. https://www.gov.uk/government/publications/malaria-prevention-guidelines-for-travellers- from-the-uk

3. Further aspects of treatment

Pre-treatment management overview

• The patient’s need for chemoprophylaxis must be appropriately assessed against their

travel destinations and any contraindications or cautions that they present with.

Adverse reactions

• Follow local SOP on adverse reactions and their management.

• Very common side effects include (≥1/10): abnormal dreams; insomnia (2).

• Common side effects include (≥1/100 to <1/10): depression; anxiety; dizziness; headache; visual impairment; vertigo; nausea, diarrhoea, abdominal pain, vomiting; pruritus (2).

• A number of other side effects with an unknown frequency have been reported: Suicide, attempted suicide, suicidal ideation and self- endangering behaviour, bipolar disorder, psychotic disorder including e.g. delusional disorder, depersonalization, mania, and schizophrenia/schizophreniform disorder, paranoia, panic attacks, confusional state, hallucinations, aggression, agitation, restlessness, mood swings, disturbance in attention; AV block, tachycardia, palpitation, bradycardia, irregular heart rate, extrasystoles, other transient conduction disorder; Stevens-Johnson syndrome, erythema multiforme, rash, erythema, urticaria, alopecia, hyperhidrosis; Oedema, chest pain, asthenia, malaise, fatigue, chills, pyrexia (2).

• Mefloquine may induce psychiatric symptoms such as anxiety disorders, paranoia, depression, hallucinations and psychosis. Psychiatric symptoms such as abnormal dreams/nightmares, acute anxiety, depression, restlessness or confusion have to be regarded as prodromal for a more serious event. Cases of suicide, suicidal thoughts and self-endangering behaviour such as attempted suicide have been reported (2).

• Patients on malaria chemoprophylaxis with mefloquine should be informed that if these reactions or changes to their mental state occur during mefloquine use, to stop taking mefloquine and seek medical advice immediately so that mefloquine can be replaced by alternative malaria prevention medication (2).

• Adverse reactions may also occur after discontinuation of the drug. In a small number of patients it has been reported that neuropsychiatric reactions (e.g. depression, dizziness or vertigo and loss of balance may persist for months or longer, even after discontinuation of the drug (2).

• Cases of polyneuropathy (based on neurological symptoms such as pain, burning, sensory disturbances or muscle weakness, alone or in combination) have been reported in patients receiving mefloquine. Mefloquine should be discontinued in patients experiencing symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness in order to prevent the development of an irreversible condition (2).

• Cases of agranulocytosis and aplastic anaemia have been reported during mefloquine therapy (2).

• For a comprehensive list of all warnings, cautions and potential adverse reactions, refer

to the current BNF and SPC (Great Britain or Northern Ireland).

Reporting procedure of adverse reactions

• Report to GP if appropriate & document in patient’s medication records.

• Follow local SOP for reporting of adverse events.

• All suspected adverse reactions must be reported via the Yellow Card scheme to the MHRA or on the website at https://yellowcard.mhra.gov.uk/

• An adverse reaction should be reported even if it is not certain that the medicine has caused it, if it is well recognised, or if other drugs were given at the same time.

• Further information is available online from https://yellowcard.mhra.gov.uk/

3. Further aspects of treatment – continued

Advice to patient / carer

Patient information

• Provide a patient information leaflet and discuss as required.

• Ensure that the patient understands the dosing schedule and emphasize the importance of adhering to the schedule to achieve effective chemoprophylaxis.

• Provide advice on & explain potential warnings & side effects and request to report them if they occur.

• Advise on possible side effects and their management. If the symptoms persist, or the patient experiences other severe symptoms then they should be advised to contact their GP, call NHS 111 or visit A&E.

  Malaria prevention

• Discuss and explain current guidelines on malaria prevention and how to recognise signs and symptoms of malaria infection. A useful tool is the widely recognised ABCD approach to malaria prophylaxis (1):

  ̵ Awareness of risk

  ̵ Bite prevention

  ̵ Chemoprophylaxis

  ̵ Diagnose malaria promptly and treat without delay

• The Advisory Committee on Malaria Prevention (ACMP) recommends the following repellents (1):

  ̵ 50% DEET based insect repellent as first choice

  ̵ 20% Picaridin based insect repellent

  ̵ Eucalyptus citriodora oil

  ̵ 3-ethylaminoproprionate

• Explain to the patient that whilst no regime can provide total protection from becoming infected, taking sensible precautions will reduce risks.

  Side-effects

• Make the patient aware that they should seek medical advice should they develop a fever or flu like symptoms during their trip or within two to three months of leaving a malarious area (5).

• Special care should be taken if driving, piloting an aircraft, operating machinery, deep sea driving or other activities that require co-ordination of small accurate movements and spatial awareness, as Lariam® can cause dizziness and loss of balance. In some people these effects persist for months after finishing their course of tablets (5).

• Under the following circumstances Lariam® should be stopped immediately and medical attention sought (5):

  • Patient experiences serious mental problems

  • Severe changes in texture and appearance of the skin, especially serious blistering and peeling that affects the mouth, eyes and genitals (Stevens Johnson syndrome)

  • Seizures or convulsions

  • Severe changes in heartbeat, including pounding and palpitations.

  • Inflammation of the lungs presented as fever, chills, cough, shortness of breath or chest pain

  • Severe liver problems which might be demonstrated by jaundice (yellowing of

skin/eyes), dark urine, light coloured stools and generalised itchiness

3. Further aspects of treatment – continued

Records to be kept

• In all cases manual records including any risk assessment forms or computerised records should include:

  ̵ Patient’s name, address and date of birth;

  ̵ Name of supplier;

  ̵ Dose, site and route of administration;

  ̵ Date of administration/supply;

  ̵ Brand name, batch number & expiry date of product;

  ̵ Confirmation that there are no contraindications; that side effects have been discussed; support literature given (if applicable) and any other advice given;

  ̵ That valid informed consent was given prior to administration/supply;

  ̵ Signature and printed name and designation (in black ink) for paper records. For computer records, ensure data authentication of practitioner delivering care;

• GP may be notified, so long as the patient has consented for personalised information to be shared.

• Pharmacy/clinic records should be stored in line with relevant legislation and local policies. Generally, records should be kept for 8 years in adults and until 25 years of age

in children, or for 8 years after a child’s death.

3. Further aspects of treatment – continued

Additional facilities / requirements

• Medication supplied using this PGD must be labelled with the same labelling requirements which patients would otherwise have received if the medicine had been supplied against a prescription and indicate in the patient’s medication record that the medicine was supplied via a PGD.

• Access to medical support (this may be via telephone).

  PGD user must:

• Be familiar with and have online access to the most recent information regarding Lariam®, such as information from the product SPC and the BNF.

• Be able to assess the patient’s capacity to understand the nature and purpose of the

  supply in order for the patient to give or refuse consent.

• Be aware of current clinical recommendations and be able to undertake supply and discuss any issues that may arise.

• Have been trained in the delivery of this medicine covered by this PGD.

• Maintain their skills, knowledge and their own professional level of competence in this area according to their individual code of professional conduct.

• Possess appropriate professional indemnity.

• Agree to work within the terms of the implementing PGD.

• Be aware of medicine handling, storage and supply guidelines.

  The superintendent/clinical lead of the implementing pharmacy/clinic will be responsible for:

• Providing adequate up-to-date clinical resources.

• Ensuring that staff using the PGD, have access to up-to-date resources.

• Ensuring that staff have received adequate training in all areas relevant to this PGD.

  Requirements for Continuing Professional Development (CPD)

• All staff involved in the implementation of this PGD should participate in adequate and appropriate CPD to ensure procedures follow the most up to date clinical guidance. Facilities and supplies to be available

• Consultations carried out under the authorisation of this PGD should be completed in a private space, physically closed off from interruption such as a pharmacy consultation room, in order to ensure patient confidentiality.

• The following should be available:

  1. Safe storage areas for medicines and equipment

  2. Clean and tidy clinical rooms that allow confidentiality and patient privacy.

  3. Copies of the current PGD

  4. Access to a current BNF and relevant SPC.

     Audit

• All health risk assessment, advice and medicine supply record forms should be stored in the pharmacy/clinic and will be audited by the implementing pharmacy/clinic in order to analyse service delivery. If the service is deemed insufficient, management staff, the superintendent/clinical lead and implementing healthcare professional will be informed

and an action plan drawn up to remedy the service.

3. Further aspects of treatment – continued

Consent

• Prior to the administration and/or supply of a medicine, consent must be obtained, preferably written, from the patient, and documented either in the patient’s medical records/notes or on an administration form.

  The key points include:

• If a patient’s fitness and suitability cannot be established, supply should be deferred.

• There is no legal requirement for consent to be in writing but written consent serves to record the decision and the discussions that have taken place.

• Consent - either written or verbal - is required at the time of each supply.

• Consent remains valid unless the patient who gave it withdraws it. If there is new information between the time consent was given and when the supply is offered, including new evidence of risk, new medicines becoming available or where there is a significant change in the patient’s condition, it may be necessary for the patient to reconfirm their consent.

• Written and verbal information should be available in a form that can be easily understood by the person who will be giving the consent. Where English is not easily understood, translations and properly recognised interpreters should be used in order that they can make informed consent.

• The attendance of a patient for the supply/administration of treatment after an invitation to attend for this purpose may be viewed as acceptance that the patient may have the treatment/administration.

• Patients should also be informed about how data on the supply will be stored, who will be able to access that information and how that data may be used.

• Where consent is either refused or withdrawn, this decision must be documented.

• Consent obtained before the occasion upon which a patient attends for the supply/administration is only an agreement for the patient to be included in this instance and does not mean that consent is in place for each future supply/administration.

4. References & Resources

For a comprehensive list of all warnings, cautions and potential adverse reactions, refer to the current BNF and SPCs.

References

1. Guidelines for malaria prevention in travellers from the UK 2021. Public Health England. [Online] June 2021. [Cited: 08 April 2022.] https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1002275/Guidelines_for_malaria_pre vention_in_travellers_from_the_UK_2021-1.pdf.

2. Summary of Product Characteristics; Larium 250mg tablets. emc (Great Britain). [Online] 07 December 2020. [Cited: 08 April 2022.] https://www.medicines.org.uk/emc/product/9670/smpc.

3. Malaria prophylaxis: Prescribing mefloquine. Clinical Knowledge Summaries: The National Institute for Health and Care Excellence.

   [Online] March 2021. [Cited: 18 March 2022.] https://cks.nice.org.uk/topics/malaria-prophylaxis/prescribing-information/mefloquine/.

4. Mefloquine. BNF; The National Institute for Health and Care Excellence. [Online] [Cited: 18 March 2022.] https://bnf.nice.org.uk/drug/mefloquine.html.

5. Patient Information Leaflet; Larium 250mg tablets. emc (Great Britain). [Online] 07 December 2020. [Cited: 08 April 2022.] https://www.medicines.org.uk/emc/files/pil.9670.pdf.

Additional resources

1. Guidelines for malaria prevention in travellers from the UK 2021. Public Health England. [Online] January 2021. [Cited: March 25, 2022.] https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1002275/Guidelines_for_malaria_pre vention_in_travellers_from_the_UK_2021-1.pdf.

2. Malaria. NHS. [Online] February 18, 2022. [Cited: March 28, 2022.] https://www.nhs.uk/conditions/malaria/.

3. Malaria fact sheet. Public Health England. [Online] December 13, 2013. [Cited: March 28, 2022.] https://www.gov.uk/government/publicatio

National Institute for Health and Care Excellence, Competency framework: For health professionals using Patient Group Directions, Published January 2014.

5. NaTHNaC Malaria fact sheet. Public Health England. [Online] January 31, 2019. [Cited: March 28, 2022.] 1. Guidelines for malaria prevention in travellers from the UK 2021. Public Health England. [Online] January 2021. [Cited: March 25, https://travelhealthpro.org.uk/disease/113/malaria.