Consumer medicine information

Mysoline

Primidone

BRAND INFORMATION

Brand name

Mysoline

Active ingredient

Primidone

Schedule

SUMMARY CMI

MYSOLINE^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using MYSOLINE?

MYSOLINE contains the active ingredient Primidone. MYSOLINE is used to control epilepsy.

For more information, see Section 1. Why am I using MYSOLINE? in the full CMI.

2. What should I know before I use MYSOLINE?

Do not use MYSOLINE if you have ever had an allergic reaction to Primidone or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use MYSOLINE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may be affected by MYSOLINE or may affect how well MYSOLINE works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use MYSOLINE?

Your doctor or pharmacist will tell you how many tablets you will need to take each day
Follow the instructions provided and use MYSOLINE until your doctor tells you to stop

More instructions can be found in Section 4. How do I use MYSOLINE? in the full CMI.

5. What should I know while using MYSOLINE?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using MYSOLINE Take your MYSOLINE regularly Tell your doctor immediately if you have any thoughts about suicide or doing harm to yourself
Things you should not do	Do not stop taking MYSOLINE, or lower change the dosage, without checking with your doctor
Driving or using machines	Be careful before you drive or use any machines or tools until you know how MYSOLINE affects you
Drinking alcohol	Be careful when drinking alcohol while you are using MYSOLINE as it may increase the effects of alcohol
Looking after your medicine	Store it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 25°C Keep your MYSOLINE tablets in the bottle until it is time to take them.

For more information, see Section 5. What should I know while using MYSOLINE? in the full CMI.

6. Are there any side effects?

MYSOLINE may have unwanted side effects in some people. If you do experience any side effects, most of them are minor and temporary. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking MYSOLINE.

If you get any of the following side effects, tell your doctor immediately or go to Accident and Emergency at your nearest hospital: Rash, itching or hives, swelling of the face, lips, tongue or throat, any thoughts of harming yourself or others, or thoughts of committing suicide.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

MYSOLINE^®

Active ingredient: Primidone

Consumer Medicine Information (CMI)

This leaflet provides important information about using MYSOLINE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using MYSOLINE.

Where to find information in this leaflet:

1. Why am I using MYSOLINE?
2. What should I know before I use MYSOLINE?
3. What if I am taking other medicines?
4. How do I use MYSOLINE?
5. What should I know while using MYSOLINE?
6. Are there any side effects?
7. Product details

1. Why am I using MYSOLINE?

MYSOLINE contains the active ingredient primidone. MYSOLINE belongs to a group of medicines called antiepileptics. These medicines are thought to work by controlling brain chemicals which send signals to nerves so that seizures do not happen.

MYSOLINE is used to control epilepsy. Epilepsy is a condition where you have repeated seizures (fits).

MYSOLINE may also be used for the treatment of other seizures and movement disorders such as partial seizures (Jacksonian seizures), myoclonic (involuntary) jerks and akinetic attacks (sudden loss of muscle tone).

MYSOLINE may be used alone, or in combination with other medicines, to treat your condition.

2. What should I know before I use MYSOLINE?

Warnings

Do not use MYSOLINE if:

you are allergic to primidone or any of the ingredients listed at the end of this leaflet
Always check the ingredients to make sure you can use this medicine
you have a rare metabolic disorder called acute intermittent porphyria

Check with your doctor if you:

have any other medical conditions such as liver, problems
kidney or lung problems
take any medicines for any other conditions

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

If you are pregnant or intend to become pregnant while taking MYSOLINE, you must talk to your doctor.

MYSOLINE can be harmful to unborn children when taken by a woman during pregnancy. It can cause birth defects and can affect the way in which the child develops as it grows. However, do not stop taking MYSOLINE unless your doctor says so as there are risks to the mother and child from uncontrolled epilepsy.

If it is necessary for you to take MYSOLINE, your doctor can help you decide whether or not to take it during pregnancy.

Talk to your doctor before breastfeeding while taking MYSOLINE.

MYSOLINE passes into breast milk and may affect your baby.

If you do breastfeed, watch your baby carefully.

If your baby becomes excessively sleepy and difficult to wake, speak to your doctor before breastfeeding again.

Contraception use

Use an effective method of contraception and consult your doctor before planning pregnancy.

MYSOLINE can seriously harm an unborn child when taken during pregnancy. If you are a female of childbearing age, you must use at least one highly effective method of contraception (such as an intra-uterine device) or two complementary forms of contraception including a barrier method should be used, without interruption during your entire treatment with MYSOLINE and for two months after stopping treatment.

Your doctor should discuss with you the most appropriate method of contraception for you.

MYSOLINE may result in a failure of the oral contraceptive pill, you should let your doctor know that you are taking it.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins, or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by MYSOLINE or may affect how well MYSOLINE works. This includes (but is not limited to):

medicines for epilepsy or convulsions
medicines used to thin your blood eg. warfarin
anti-infective, anti-viral and anti-fungal medicines
medicines that affect the heart rhythm
medicines that are derived from natural or synthetic hormones
medicines to treat pain
medicines to treat mood disorders, including anti-depressants and anti-psychotics
medicines for the treatment of cancer
oral contraceptives (birth control pills)

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect MYSOLINE.

4. How do I use MYSOLINE?

How much to take

your doctor or pharmacist will tell you how many tablets you will need to take each day. Your dose will be adjusted according to your response
follow the instructions provided and use MYSOLINE until your doctor tells you to stop

When to take MYSOLINE

MYSOLINE is usually taken twice a day
MYSOLINE should be used regularly at the same time each day
if you have trouble remembering when to take your medicine, ask your pharmacist for some hints

If you forget to use MYSOLINE

MYSOLINE should be used at the same times each day.
if you miss your dose at the usual time, take it as soon as you remember, as long as it is at least 6 hours before the next dose is due. Then go back to taking it as you would normally
if it is less than 6 hours to your next dose, skip the dose you missed and take your next dose when you are meant to. Then go back to taking it as you would normally
do not take a double dose to make up for the dose you missed

If you are not sure what to do, ask your doctor or pharmacist.

If you use too much MYSOLINE

If you think that you or anyone else have taken too much MYSOLINE, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre (by calling 13 11 26), or
contact your doctor or pharmacist, or
go to the Emergency Department at your nearest hospital

You should do this even if there are no signs of discomfort or poisoning.

If you take too many MYSOLINE tablets you might feel unsteady and drowsy. You may lose consciousness.

5. What should I know while using MYSOLINE?

Things you must do

Tell any other doctor, dentist, or pharmacist you visit that you are taking MYSOLINE.

Tell your doctor immediately if you:

have any thoughts about suicide or doing harm to yourself

Warning signs of suicide:
All thoughts or talk about suicide or violence are serious. If you or someone you know is showing the following warning signs, either contact your doctor or a mental health advisor right away or go to the nearest hospital for treatment:

thoughts or talk about death or suicide
thoughts or talk about self-harm or doing harm to others
any recent attempts of self-harm
an increase in aggressive behaviour, irritability or agitation

Things you should not do

do not stop taking MYSOLINE, or change the dosage, without checking with your doctor

Suddenly stopping MYSOLINE may cause fits or a withdrawal reaction.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how MYSOLINE affects you.

MYSOLINE can make some people sleepy, and it may take you longer to react in certain situations.

Drinking alcohol

Be careful when drinking alcohol while you are using MYSOLINE.

MYSOLINE may increase the effects of alcohol.

Please talk to your doctor or pharmacist about these things if you think they may bother you.

Looking after your medicine

keep your MYSOLINE tablets in the bottle until it is time to take them. If you take MYSOLINE out of the bottle it will not keep well
store below 25°C

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat, or sunlight where the temperature stays below 25°C; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking MYSOLINE.

MYSOLINE helps most people with seizures, but it may have unwanted side effects in some people If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Your doctor may perform regular tests or other observations to check for changes to your blood levels (anaemia, thrombocytopenia), vitamin D levels, and bone mineral density.

Less serious side effects

Less serious side effects

What to do

Gut and digestion:

nausea or vomiting

Other:

drowsiness or tiredness
dizziness or unsteadiness when walking
headache
visual disturbances
painful joints
worsening of your epilepsy symptoms

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Signs of an allergic reaction such as:

rash, itching or hives
swelling of the face, lips, tongue or throat

Signs of liver problems such as:

yellowing of the skin and/or eyes

Signs of unusual bleeding such as:

bleeding or bruising under the skin

Mental health related:

thoughts or talk about suicide or violence
thoughts or talk about self-harm or doing harm to others
attempts at self-harm
increase in aggressive behaviour, irritability or agitation
unusual changes in moods
worsening of depression

Skin:

worsening or blistering rash

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

MYSOLINE is only available with a doctor's prescription.

What MYSOLINE contains

Active ingredient (main ingredient)	primidone
Other ingredients (inactive ingredients)	povidone carmellose calcium gelatin (E441) magnesium stearate (E572) stearic acid (E570)

Do not take this medicine if you are allergic to any of these ingredients.

What MYSOLINE looks like

MYSOLINE tablets are white, or virtually white, round biconvex, uncoated tablets that are plain on one side with a bisecting line on the other side. "M" is printed on either side of the bisecting line. (Aust R 11231).

Who distributes MYSOLINE

Link Medical Products Pty Ltd
5 Apollo Street
Warriewood, NSW 2102
AUSTRALIA

This leaflet was prepared in January 2022

Published by MIMS March 2022

BRAND INFORMATION

Brand name

Mysoline

Active ingredient

Primidone

Schedule

1 Name of Medicine

Primidone.

2 Qualitative and Quantitative Composition

Each Mysoline tablet contains 250 mg primidone as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets BP.
White or virtually white, round biconvex, uncoated tablets, intagliated with an "M" on each side of a bisecting line on one face and plain on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Management of grand mal and psychomotor (temporal lobe) epilepsy.
It is also of value in the management of focal or Jacksonian seizures, myoclonic jerks and akinetic attacks.

4.2 Dose and Method of Administration

Treatment must always be planned on an individual basis. In many patients, it will be possible to use Mysoline alone, but in some patients, Mysoline will need to be combined with other anticonvulsants.
Mysoline is usually given twice daily. Begin with ½ tablet once daily late in the evening. Every three days, increase the daily dosage by ½ tablet until the patient is receiving 2 tablets daily. Thereafter, every three days, increase the daily dosage by 1 tablet in adults or ½ tablet in children under 9 years, until control is obtained or the maximum tolerated dosage is being given. This may be as much as 6 tablets/day in adults or 4 tablets/day in children. See Table 1.
The total daily dose is usually best divided and given in two equal amounts, one in the morning and the other in the evening. In certain patients, it may be considered advisable to give a larger dose when the seizures are more frequent. For instance, if the attacks are nocturnal, then all or most of the day's dose may be given in the evening; or if the attacks are associated with some particular event, such as menstruation, a slight increase in dose at the appropriate time is often beneficial.

Patients taking other anticonvulsants.

Where a patient's attacks are not efficiently well controlled with other anticonvulsants, or disturbing side effects have arisen, Mysoline may be used to augment or replace existing treatment. First add Mysoline to the current anticonvulsant treatment by the method of gradual introduction described previously. When a worthwhile effect has been achieved and the amount of Mysoline being given has been built up to at least half the estimated requirement, withdrawal of the previous treatment can then be attempted. This should be done gradually over a period of two weeks, during which time it may be necessary to increase the Mysoline dosage to maintain control. Withdrawal of previous treatment should not be too rapid or status epilepticus may occur. Where phenobarbitone formed the major part of the previous treatment, however, both its withdrawal and Mysoline substitution should be made earlier, so as to prevent excessive drowsiness from interfering with accurate assessment of the optimum dosage of Mysoline.

4.3 Contraindications

Hypersensitivity or allergic reactions to primidone, or to any of the excipients listed in Section 6.1 List of Excipients.
Acute intermittent porphyria.

4.4 Special Warnings and Precautions for Use

Primidone should be given with caution and may be required in reduced dosage in patients with impaired respiratory function.
Primidone, as with other anticonvulsants, can induce liver enzymes and although there is insufficient evidence to suggest a causal relationship, there is a theoretical risk of hepatic damage.

Women of childbearing potential.

Primidone is extensively metabolised to phenobarbital. As a consequence, primidone may cause fetal harm when administered to a pregnant woman. Prenatal exposure to primidone may increase the risk for congenital malformations and adverse developmental outcomes (see Section 4.6).
Primidone should not be used in women of childbearing potential unless the potential benefit is judged to outweigh the risks following consideration of other suitable treatment options.
Women of childbearing potential, women planning pregnancy, and pregnant women should be fully informed of the potential risk to the fetus if they take primidone during pregnancy.

Vitamin D.

Primidone may affect vitamin D metabolism, which may predispose to the development of bone disease. There are reports that long-term use may lead to a reduction of bone mineral density and therefore development of osteoporosis (Petty, S.J. et al, Neurology, 65: 1358-1363, 2005). Patients on long-term treatment should be monitored for bone density and supplementation with vitamin D should be considered.

Aggravated convulsions.

As with other antiepileptic drugs, some patients may experience, instead of an improvement, a worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with primidone. For patients on primidone, cases of these aggravations may be indicative of an inadequate choice of treatment for the epileptic syndrome, a result of a change of the concomitant anti-epileptic treatment or a pharmacokinetic interaction, a toxicity or overdose.

Treatment cessation.

Sudden withdrawal of a treatment at efficient anti-epileptic doses may induce convulsive fits and epilepticus status, mainly in cases of alcoholism.
Primidone is a potent central nervous system depressant and is partially metabolised to phenobarbitone. After prolonged administration there is a potential for tolerance, dependence and a withdrawal reaction on abrupt cessation of treatment.

Suicidal behaviour and ideation.

Antiepileptic drugs, including primidone, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo controlled clinical trials (mono and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing primidone or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour, and should be advised of the need to be alert for the emergence of worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour, or thoughts about self harm. Behaviours of concern should be reported immediately to the treating doctor.

Severe skin reactions.

Life threatening cutaneous reactions, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with the use of primidone. Patients should be advised of the signs and symptoms and monitored closely for skin reactions.
The highest risk for occurrence of SJS or TEN is within the first weeks of treatment. If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters of mucosal lesions) are present, primidone treatment should be discontinued.
If the patient has developed SJS or TEN with the use of primidone (or phenobarbital), primidone must not be re-started in this patient at any time.

Use in hepatic impairment.

Primidone should be given with caution and may be required in reduced dosage in patients with impaired hepatic function.

Use in renal impairment.

Primidone should be given with caution and may be required in reduced dosage in patients with impaired renal function.

Use in the elderly.

Primidone should be given with caution and may be required in reduced dosage in the elderly.

Use in debilitated patients.

Primidone should be given with caution and may be required in reduced dosage in debilitated patients.

Paediatric use.

Primidone should be given with caution and may be required in reduced dosage in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Both primidone and its major metabolite, phenobarbitone, induce liver enzyme activity; both primidone and phenobarbitone are strong inducers of cytochrome P450. This may lead to altered pharmacokinetics in concomitantly administered drugs including other anticonvulsant drugs, e.g. phenytoin and coumarin anticoagulants. Such interactions may lead to life threatening situations due to the risk of decreased plasma concentrations and consequently, lack of efficacy of co-administered medications.
Blood levels of both primidone and any additional anticonvulsant agent may be altered by concomitant administration.

Concomitant use not recommended.

Risk of decreased plasma concentrations due to increased metabolism induced by primidone for:

Drugs affecting nervous system* (except anti-epileptics).

Lurasidone, mianserin, oxycodone, quetiapine, sertraline.

Anti-infective agents.

Delamanid, telithromycin, bedaquiline.

Anti-neoplastic agents.

Tyrosine kinase inhibitors, ifosfamide (+ risk of increased neurotoxicity of ifosfamide due to increased metabolism induced by primidone).

Antivirals.

Cobicistat, daclatasvir, dasabuvir, ledipasvir, nelfinavir, rilpivirine, ombitasvir + paritaprevir, sofosbuvir, telaprevir, boceprevir, simeprevir.

Antifungal agents.

Voriconazole, isavuconazole, itraconazole.

Anticoagulant drugs.

Apixaban, dabigatran, rivaroxaban, ticagrelor.

Cardiovascular agents.

Bosentan, nimodipine, dronedarone, macitentan, ranolazine.

Hormonal agents.

Abiraterone, ulipristal.

Other therapeutic classes.

Alcohol (+ increased risk of sedative effects of primidone and alcohol), ivacaftor, praziquantel.
Risk of decreased primidone plasma concentrations and risk of lack of efficacy for: St John's wort.

Precaution - concomitant use may require dosage adjustment.

Risk of decreased plasma concentrations due to increased metabolism induced by primidone for:

Other anti-epileptics.

Carbamazepine; felbamate; lamotrigine; oxcarbazepine (+ risk of decreased plasma levels of primidone by increased metabolism induced by oxcarbazepine); perampanel; phenytoin (+ risk of increased phenobarbital concentrations and possible toxicity. Possible toxicity with phenytoin on stopping primidone); stiripentol, tiagabine, valproic acid, zonisamide.

Drugs affecting nervous system* (except anti-epileptics).

Benzodiazepines, methadone, opioid agents (including fentanyl).

Anti-infective agents.

Doxycycline, metronidazole, quinine (+ risk of increased phenobarbital concentrations and possible toxicity).

Anti-neoplastic agents.

Cabazitaxel, docetaxel, irinotecan, procarbazine (+ risk of increased hypersensitivity reactions: hypereosinophilia, rash).

Antivirals.

Dolutegravir; maraviroc; protease inhibitors in combination with ritonavir (amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir, tipranavir): risk of decreased primidone concentrations due to CYP3A4 significant inhibition properties of the combination protease inhibitors ritonavir.

Antifungal agents.

Albendazole, posaconazole.

Anticoagulant drugs.

Antivitamin K drugs (acenocoumarol, phenindione, warfarin): INR monitoring required.

Cardiovascular agents.

Calcium channel blockers; beta-blockers (metoprolol, propranolol); class I A antiarrhythmic, ivabradine, propafenone.

Hormonal agents.

Androgens; glucocorticosteroids and mineralocorticosteroids; thyroid hormones.

Other therapeutic classes.

Non-contraceptive estrogens; folates; immunosuppressant agents (cyclosporin, tacrolimus, sirolimus, everolimus); iron-chelators (deferasirox); theophylline.
Breakthrough bleeding and failure of contraceptive therapy have been noted in patients taking anticonvulsant drugs and oral contraceptive steroids.
*The effects of other CNS depressants (e.g. alcohol and barbiturates) may be enhanced by the administration of primidone.

4.6 Fertility, Pregnancy and Lactation

Women of childbearing potential.

Primidone should not be used in women of childbearing potential unless the potential benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options.
Women of childbearing potential should be informed of and understand the risk of potential harm to the fetus associated with primidone use during pregnancy and the importance of planning a pregnancy.
A pregnancy test to rule out pregnancy should be considered prior to commencing treatment with primidone in women of childbearing potential.
Women planning a pregnancy should be advised to consult in advance with their physician so that specialist medical advice can be provided, and appropriate alternative treatment options can be discussed prior to conception and before contraception is discontinued.
Women should be advised to contact their doctor immediately if they become pregnant or think they may be pregnant and are taking primidone.

Contraception.

Women of childbearing potential should use effective contraception during treatment with primidone and for two months after stopping treatment. Due to enzyme induction, primidone may result in a failure of the therapeutic effect of oral contraceptive drugs (see Section 4.5).
Women should be advised that at least one highly effective method of contraception (such as an intra-uterine device) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, involving the patient in the discussion, when choosing the contraception method.

Effects on fertility.

No data available.
(Category D)
Primidone is extensively metabolised to phenobarbital. Phenobarbital metabolites readily cross the placenta following oral administration and are distributed throughout fetal tissue.
It is, recommended that:
Women on antiepileptic drugs (AEDs) receive pre-pregnancy counselling with regard to the risk of congenital malformations and adverse developmental outcomes.
AEDs should be continued during pregnancy at the lowest effective dose and monotherapy should be used if appropriate.
Adequate folic acid supplementation should be discussed as part of pre-pregnancy and pregnancy counselling.
Specialist prenatal diagnosis including detailed mid-trimester ultrasound should be considered.
Specialist medical advice regarding the potential risks to a fetus caused by both seizures and antiepileptic treatment should be given to all women of childbearing potential taking antiepileptic treatment, and especially to women planning pregnancy and women who are pregnant.
Antiepileptic treatment should be reviewed regularly and especially when a woman is planning to become pregnant. In pregnant women being treated for epilepsy, sudden discontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child.
Primidone therapy in pregnant women with epilepsy presents a risk to the fetus due to the major and minor congenital defects including congenital craniofacial and cardiac defects, digital abnormalities and, less commonly, cleft lip and palate associated with the phenobarbital metabolites produced from primidone.
Studies in women with epilepsy who were exposed to phenobarbital during pregnancy identified a frequency of major malformations of 6-7% in their offspring compared to the background rate in the general population of 2-3%. Studies have found the risk of congenital malformations following in-utero exposure to phenobarbital to be dose-dependent, however, no dose has been found to be without risk. Therefore, the lowest effective dose of primidone (and phenobarbital) should be used.
The use in pregnancy of primidone, phenobarbitone or methylphenobarbitone has been associated with minor craniofacial defects, fingernail hypoplasia and developmental disability.

In neonates.

Data from a registry study suggest an increase in the risk of infants born small for gestational age or with reduced body length to women with epilepsy who were exposed to phenobarbital during pregnancy compared to women exposed to lamotrigine monotherapy during pregnancy. As primidone is extensively metabolised to phenobarbital, this is a potential risk for infants exposed to primidone.
Haemorrhage at birth and addiction are also a risk. Prophylactic treatment with vitamin K1 for the mother before delivery (as well as the neonate) is recommended and the neonate should be monitored for signs of bleeding.
During breastfeeding, the baby should be monitored for sedation.

4.7 Effects on Ability to Drive and Use Machines

As with most other anticonvulsants, patients who drive vehicles or operate machinery should be aware of the possibility of impaired reaction time.

4.8 Adverse Effects (Undesirable Effects)

If side effects do appear, they are generally confined to the early stages of treatment, when patients frequently feel drowsy and listless.
Visual disturbances, nausea, headache, dizziness, vomiting, nystagmus and ataxia have been reported, but these are usually transient even when pronounced. On occasions, an idiosyncratic reaction may occur which involves these symptoms in an acute and severe form necessitating withdrawal of treatment. Dermatological reactions including severe skin eruptions and, rarely, systemic conditions (e.g. systemic lupus erythematosus) have been reported. Occasional cases of arthralgia and, rarely, personality changes (which may include psychotic reactions) have been reported. As with phenobarbitone, in rare cases Dupuytren's contracture has been reported in patients administered Mysoline.
Exceptionally, as with phenytoin and phenobarbitone, megaloblastic anaemia may develop requiring discontinuation of primidone. This condition may respond to treatment with folic acid and/or cyanocobalamin (vitamin B₁₂). There have been isolated reports of other blood dyscrasias.
The following adverse events have been observed in patients taking primidone at an unknown frequency: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), hypersensitivity syndrome, decreased bone density, osteopenia and fractures in patients on long term therapy, apathy, megaloblastic anaemia, leucopenia, thrombocytopenia, lymphadenopathy and exfoliative dermatitis. See Section 4.4 Special Warnings and Precautions for Use, Severe skin reactions.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Primidone is metabolised extensively to phenobarbitone, and overdosage leads to various degrees of CNS depression which, depending on the dose ingested, may include ataxia, loss of consciousness, respiratory depression and coma.

Treatment.

Treatment should include supportive measures. There is no specific antidote.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Animal studies have indicated that the anticonvulsant properties of Mysoline are attributable partly to primidone itself and partly to its metabolites phenobarbitone and phenylethylmalonamide. The drug reduces the sensitivity of the central nervous system to fit inducing stimuli, but its precise mode of action is obscure, although enhancement of release of inhibitory transmitters may possibly occur.
Like phenobarbitone and phenytoin, Mysoline modifies the maximal (tonic-clonic) seizure pattern induced in rats by electrical stimulation, and at 5 mg/kg it is twice as potent as phenobarbitone in abolishing the tonic extensor component of the seizure.
Mysoline also has the ability to raise the threshold for minimal electroshock seizures in both normal and hyponatraemic animals, and to prevent experimental psychomotor seizures in mice and rats. Mysoline has been shown to be an effective antagonist to leptazol induced convulsions. Unlike phenytoin, it will prevent the tonic component of maximal convulsions as well as raise the seizure threshold.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

The rate of absorption of primidone in humans is relatively rapid, though somewhat variable between individuals. In epileptic patients a single 500 mg dose gave a peak plasma concentration of 2.7 ± 0.4 microgram/mL, even though the time to peak varied markedly. The elimination half-life in epileptic patients is 8 ± 1 hours, and similar values have been obtained in healthy volunteers and in epileptic children. In uraemic subjects, the half-life increased to 13.9 hours, but this reduced to 5.1 hours during dialysis. Steady-state drug levels in chronic seizure patients (3.2 to 12.7 microgram/mL) were directly proportional to the daily dose (250 to 1,250 mg).

Metabolism.

Metabolism involves conversion to two major metabolites, phenylethylmalonamide (PEMA) and phenobarbitone (PB), both of which have some degree of anticonvulsant activity. Metabolism to PB is slow and not linearly related to dose. Conversion to PEMA is proportional to dose and this compound is cleared with an apparent half-life of 22 to 24 hours. The hydroxylated parent drug has also been identified as a minor metabolite.

Distribution.

Primidone and its metabolites readily cross the blood brain barrier with ratios in cerebrospinal fluid/plasma of 1.1, 0.8 and 0.4 for parent drug, PEMA and PB, respectively. Penetration of brain tissue has also been demonstrated with tissue/ plasma ratios of about 1 for parent drug and PB. Primidone also crosses the human placenta.

Excretion.

In a group of epileptic children, 92% of the administered dose could be accounted for by parent drug and metabolites in urine, indicating that renal excretion was the major route of elimination and suggesting virtually complete oral bioavailability.
In contrast to PB, primidone and PEMA are not bound to plasma proteins to any significant extent.

5.3 Preclinical Safety Data

Reproductive toxicity.

Animal studies have shown that primidone is teratogenic and impairs post-natal development at doses considered to be clinically relevant. Teratogenic effects in mice included palatal defects, enlargement of cerebral ventricles, club foot, open eyes and haemorrhages within the subarachnoid space. Primidone was also shown to be embryo lethal in mice and rats at clinically relevant doses. Post-natal development effects include impairment of memory and learning development in male rats from litters of dosed female rats. Effects on fertility in animals have been observed at doses considered to be clinically relevant. Primidone induced a reduction in seminal vesicle weight and an increase in estrous cycle length in mice. In a 5-day study in male mice, primidone induced a dose-dependent increase in sperm-head abnormalities.

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Povidone, carmellose calcium, gelatin (E441), magnesium stearate (E572), stearic acid (E570).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

5 years.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light and moisture.

6.5 Nature and Contents of Container

Mysoline is available in 100 tablet, and 200 tablet bottles.
AUST R 11231.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Mysoline is a highly stable, crystalline substance with a slightly bitter taste. It is only sparingly soluble in water (approximately 60 mg/100 mL at 37°C) and in most organic solvents. Unlike phenobarbitone, it does not possess any acidic properties.

Chemical structure.

Chemical Name: 5-ethyl-5-phenyl-2,3-dihydropyrimidine-4,6(1H,5H)-dione.
Molecular formula: C₁₂H₁₄N₂O₂. MW: 218.3.

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Mysoline

Primidone

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Mysoline Tablets 250 mg