Package leaflet: Information for the patient

FRISIUM 10 mg hard capsules

clobazam
Read this leaflet carefully before you take this medicine because it contains
important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, consult your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it could be harmful.
If you experience any adverse reactions, including those not listed in this leaflet, consult your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Frisium is and what it is used for
What you need to know before taking Frisium
How to take Frisium
Possible side effects
How to store Frisium
Contents of the pack and other information

1. What Frisium is and what it is used for

Frisium contains clobazam, which belongs to a class of medicines called "anxiolytics; benzodiazepines".
Frisium is indicated for the treatment of anxiety, tension, and other anxiety-related disorders (somatic or psychiatric manifestations), as well as difficulty sleeping or falling asleep (insomnia).
Medicines of the same class as Frisium (benzodiazepines) are indicated only when the disorder is severe, disabling, and causes severe distress to the patient.

2. What you should know before taking Frisium

Do not take Frisium

if you are allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6).
if you suffer from a disease characterised by severe muscle weakness (severe myasthenia gravis).
if you suffer from serious respiratory problems (severe respiratory insufficiency, e.g. severe chronic obstructive pulmonary disease).
if you suffer from serious liver problems (severe hepatic insufficiency).
if you suffer from breathing pauses during sleep (sleep apnoea syndrome).
if you suffer from lack of coordination in body movements (spinal and cerebellar ataxia).
if you are breastfeeding (see "Pregnancy and Breastfeeding").
if it is for a child under 3 years of age.

Warnings and precautions
Talk to your doctor or pharmacist before taking Frisium, and especially:

before taking any non-medicinal product containing cannabidiol, as it may increase the adverse effects of clobazam.
if you are taking any medicinal product containing cannabidiol, as it may increase the adverse effects of clobazam.

Patients with metabolic disorders (poor CYP2C19 metabolisers)
If you have a metabolic disorder known as “poor CYP2C19 metaboliser”, your doctor will appropriately adjust the dose of Frisium (e.g. a low starting dose).

Alcohol
Do not consume alcohol during treatment with Frisium, due to the increased risk of excessive sedative effects (sedation) and other adverse effects.

Tolerance
After repeated use for several weeks, a certain reduction in the effect of this medicine may occur.

Dependence
The use of medicines of the same class as Frisium (benzodiazepines) may lead to dependence (need to continue taking the medicine). The risk of dependence increases with dose and duration of treatment; it is higher in patients with a history of drug or alcohol abuse.
If you have previously been dependent on drugs or alcohol, using Frisium, as with all other medicines belonging to the benzodiazepine class, may carry a higher risk of developing dependence.
The risk of dependence exists even if you take clobazam daily for only a few weeks, and may occur not only with particularly high doses but also with the recommended therapeutic dose.
Avoid using Frisium for prolonged periods without interruption, as dependence may develop.
If physical dependence has developed, abrupt discontinuation of treatment will be accompanied by the following withdrawal symptoms:

headache (cephalalgia),
muscle pain,
extreme anxiety,
tension,
restlessness,
confusion,
irritability.

In severe cases, the following symptoms may also occur:

feeling detached from reality (derealisation),
feeling estranged from one's own body (depersonalisation),
hearing disturbances with intolerance to noise (hyperacusis),
numbness,
tingling in the extremities,
hypersensitivity to light,
hypersensitivity to noise and physical contact,
hallucinations,
psychiatric disturbances (symptomatic psychosis) or epileptic seizures.

Other possible symptoms include:

depression,
insomnia,
increased dreaming,
sweating,
persistent ringing in the ears (tinnitus),
involuntary movements,
nausea,
vomiting,
altered sensation (paraesthesia),
perceptual disturbances,
abdominal and muscular cramps,
tremor,
muscle pain (myalgia),
agitation,
palpitations,
increased heart rate (tachycardia),
panic attacks,
dizziness,
increased reflexes (hyperreflexia),
short-term memory loss,
increased body temperature (hyperthermia).

Rebound insomnia and anxiety
Upon discontinuation of the medicine, a transient condition may occur, characterised by the return, in an intensified form, of the symptoms that led to treatment. This condition may be accompanied by other reactions, including mood changes, anxiety, restlessness, or sleep disturbances.
This is more likely to occur if the medicine is stopped abruptly; therefore, discontinue treatment with Frisium gradually.
It is important that you are aware of the possibility of such symptoms occurring if you stop treatment with Frisium.

Duration of treatment
The duration of treatment should be as short as possible (see "How to take Frisium"), according to your doctor’s advice, but should not exceed four weeks for insomnia and eight to twelve weeks for anxiety, including the period of gradual withdrawal. The treatment duration should not be extended beyond this period without your doctor re-evaluating your condition.
At the beginning of treatment, your doctor will explain that this treatment will be of limited duration and how you should gradually reduce the dose.
Furthermore, your doctor will warn you that it is not advisable to abruptly switch to other medicines similar to Frisium, known as “benzodiazepines with short duration of action”, as this change may cause withdrawal symptoms.
As with other benzodiazepines, in case of prolonged treatment, the therapeutic benefit should be periodically assessed due to the possible development of tolerance and dependence.

Memory disturbances (amnesia)
Frisium may cause memory disturbances (anterograde amnesia), both when used at normal doses and especially at higher doses. This occurs more frequently several hours after taking the medicine: to reduce the risk, ensure you can sleep uninterrupted for 7–8 hours (see "Possible side effects").

Psychiatric reactions and “paradoxical” reactions
When using medicines similar to Frisium (benzodiazepines), reactions such as the following may occur:

restlessness,
agitation,
irritability,
aggression,
dysphoria,
anger,
nightmares,
hallucinations,
psychosis,
behavioural changes.

If these symptoms occur, contact your doctor and stop using Frisium.
These reactions are more likely to occur in children and elderly patients, as well as in patients with a condition known as “organic brain syndrome” (reduced mental function).

Severe skin reactions
Severe, potentially life-threatening skin diseases (Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with the use of Frisium in both children and adults. These conditions initially present as round red spots or circular patches, often accompanied by blisters, skin peeling, particularly on the central body, mouth ulcers, throat, nose and genital sores, red and swollen eyes (conjunctivitis). Flu-like symptoms are often present.
In most cases, these effects occur when Frisium is used concomitantly with other medicines, including those used in the treatment of epilepsy (antiepileptics). The highest risk of severe skin reactions occurs within the first 8 weeks of treatment.
If these symptoms appear, stop treatment with Frisium and consult your doctor immediately. If you have developed these symptoms while using Frisium, you must not use the medicine again (see "Possible side effects").

Elderly patients
If you are elderly, taking medicines like Frisium may increase the risk of falls due to adverse effects such as lack of muscle coordination (ataxia), muscle weakness, dizziness, drowsiness, fatigue and tiredness. Falls can lead to serious injuries.
If you are elderly, you will receive a lower dose of the medicine (see "How to take Frisium").

Patients with severe respiratory disorders (chronic respiratory insufficiency)
If you suffer from severe respiratory disorders (chronic respiratory insufficiency), your doctor will prescribe a lower dose due to the risk of worsening breathing (respiratory depression; see also “Do not take Frisium”). If you suffer from a respiratory disorder called “acute respiratory insufficiency”, your doctor will periodically monitor your respiratory function.
Clobazam is contraindicated in patients with severe respiratory insufficiency (see “Do not take Frisium”).

Muscle weakness
Frisium may cause muscle weakness. Therefore, if you already suffer from muscle weakness, your doctor will monitor you and may reduce your clobazam dose. Do not take Frisium if you suffer from a disease characterised by severe muscle weakness called “myasthenia gravis” (see “Do not take Frisium”).

Patients with severe liver impairment (hepatic insufficiency)
If you suffer from severe liver impairment (severe hepatic insufficiency) and/or a brain disorder called “encephalopathy”, you should take this medicine with caution, as Frisium, like all medicines of the same class (benzodiazepines), may trigger a condition called “hepatic encephalopathy” (brain disturbances caused by severe liver dysfunction).
If your liver and kidney function are impaired, your doctor will reduce your dose, as you may have increased sensitivity to clobazam and a higher likelihood of adverse effects. In case of prolonged treatment, your doctor will perform frequent checks of liver and kidney function.
Frisium and medicines of the same class (benzodiazepines) are not recommended for the primary treatment of psychiatric illness (psychosis). Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (due to the risk of suicide).
Some studies have shown an increased risk of suicidal thoughts, suicide attempts and suicide in patients taking certain sedatives and hypnotics, including this medicine.
However, it has not been established whether this is caused by the medicine or whether there may be other reasons.
If you have suicidal thoughts, contact your doctor as soon as possible for further advice (see section 4).
Use Frisium and medicines of the same class (benzodiazepines) with extreme caution if you have previously abused drugs or alcohol.

Children and adolescents
Frisium must not be administered to children under 3 years of age.
In older children, Frisium should not be administered without careful evaluation by the doctor of the actual need for treatment, and the duration of treatment should be as short as possible.

Other medicines and Frisium
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Concomitant use of Frisium and opioids (strong analgesics, medicines for addiction therapy, and some cough medicines) increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may be life-threatening. For this reason, concomitant use should only be considered when other treatment options are not possible.
However, if your doctor prescribes Frisium together with opioids, the dose and duration of concomitant treatment must be limited by your doctor.
Inform your doctor about all opioid medicines you are taking and carefully follow the doctor’s dosage recommendations. It may be helpful to inform friends or family members to watch for the signs and symptoms listed above.
Contact your doctor if you experience such symptoms.

Be cautious when taking Frisium with:

medicines for mental disorders (antipsychotics),
hypnotics,
anxiolytics/sedatives,
antidepressants,
pain medicines known as “narcotic analgesics”,
antiepileptics,
anaesthetics,
allergy medicines that cause drowsiness (sedating antihistamines).

Combining Frisium with these medicines may increase the depressant effect on the Central Nervous System.
Particular caution is required when using Frisium if adverse effects are caused by these medicines or by lithium.
The effects of Frisium may be influenced by, or may influence, the following medicines:

Anticonvulsant medicines (anticonvulsants)
If Frisium is used simultaneously with anticonvulsants in epilepsy treatment, your doctor will monitor you carefully with an electroencephalogram (EEG monitoring) and adjust the dosage, as interactions with anticonvulsant therapy may occur.
If you are taking Frisium with a medicine called “valproic acid” or a medicine called “phenytoin”, an increase in blood levels of these drugs may occur, so your doctor will perform appropriate monitoring.

If you are taking Frisium together with a medicine called “Stiripentol”, you may experience increased blood levels of Frisium, with a risk of overdose. Your doctor will carefully monitor the dose of Frisium and, if necessary, adjust it.

Medicines for moderate to severe pain (narcotic analgesics)
If you are using Frisium together with narcotic analgesics, increased euphoria may occur, potentially increasing the risk of dependence.
Muscle relaxants
Using Frisium together with these medicines, including nitrous oxide, may enhance their effects.
Inhibitors of a protein called “CYP2C19”
Medicines that reduce the activity of a protein called “CYP2C19” may affect the effect of Frisium. A dose adjustment of Frisium may be necessary. Inform your doctor if you are taking any of the following medicines:
products containing cannabidiol (medicinal or non-medicinal products),
ticlopidine, an antiplatelet medicine used to prevent blood clots,
fluconazole, used to treat fungal infections,
fluvoxamine, used to treat depression,
omeprazole, used to treat stomach upset.
medicines metabolised by a protein called “CYP2D6” (CYP2D6 substrates), e.g. dextromethorphan, pimozide, paroxetine, nebivolol. A dose adjustment of these medicines may be necessary.

The following combinations should be considered with caution:

buprenorphine (used for pain): increased risk of respiratory depression, which may be fatal. Your doctor will carefully assess the need for this combination and inform you of the importance of adhering to prescribed doses;
clozapine (used for mental disorders): increased risk of collapse with respiratory and/or cardiac arrest.

The administration of theophylline or aminophylline (used for asthma) may reduce the effects of medicines belonging to the same class as Frisium (benzodiazepines).

Frisium with alcohol
Do not take Frisium with alcohol. Consuming alcohol together with Frisium may increase its effects, negatively affecting your ability to drive or operate machinery.

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
Frisium, like all benzodiazepines, must not be administered during childbirth or while breastfeeding.

The use of this medicine is not recommended during pregnancy and in women of childbearing age who are not using contraception.
If you find out you are pregnant or are planning to have a baby, consult your doctor immediately to reassess the need for treatment. Do not stop taking Frisium without speaking to your doctor.

Pregnancy
A large amount of data has not shown malformations associated with the use of benzodiazepines.
However, some studies have indicated a potential increased risk of cleft lip and palate in newborns compared to the general population.
Cleft lip and palate (also known as “hare lip”) is a birth defect caused by incomplete fusion of the palate and upper lip.
Reduced fetal movement and variability in fetal heart rate may occur after taking clobazam during the second and/or third trimester of pregnancy.
If Frisium is taken towards the end of pregnancy or during childbirth, the baby may show drowsiness (sedation), muscle weakness (hypotonia or “floppy infant syndrome”), low body temperature (hypothermia), feeding difficulties (feeding problems leading to poor weight gain), and breathing problems (respiratory depression, sometimes severe).
If taken regularly towards the end of pregnancy, the baby may show withdrawal symptoms such as agitation or tremors. In such cases, the newborn must be closely monitored during the postnatal period.

Breastfeeding
Do not take Frisium while breastfeeding, as, like all medicines of the same class (benzodiazepines), it is excreted in breast milk.

Driving and using machines
At higher doses and in case of individual sensitivity, Frisium may affect reaction ability; this should be particularly considered if alcohol is consumed concurrently.
Sedation, memory loss (amnesia), impaired concentration, and muscle function may negatively affect the ability to drive and operate machinery. If sleep duration has been insufficient, the likelihood of impaired vigilance may be increased.

Frisium contains lactose
If your doctor has diagnosed you with an intolerance to certain sugars, contact them before taking this medicine.

3. How to take Frisium

Take this medicine exactly as directed by your doctor or pharmacist. If
you have any doubts, consult your doctor or pharmacist.
The dosage and duration of treatment must be individually adjusted according to the physician's judgment,
depending on the indication, severity of the clinical condition, and individual response variability.
Treatment should be initiated with the lowest dose.
The maximum dose should not be exceeded.
You will be monitored regularly at the beginning of treatment so that, if necessary, the dose or frequency of administration can be reduced to prevent overdose due to accumulation.
The recommended dose is:

Adults: Generally 2 capsules per day, increased if necessary to 3 capsules per day. In particularly severe cases, the daily dosage may be further increased at the physician's discretion. Once clinical improvement has been achieved, the dosage may be reduced.
For elderly or debilitated patients, a daily dose of 1 capsule is often sufficient.
If the daily dose is divided throughout the day, the largest single dose should be administered in the evening before bedtime. Daily doses up to 30 mg may also be given as a single dose at bedtime.
Patients with impaired hepatic and/or renal function: In these patients, increased reactivity and higher sensitivity to adverse effects may occur. Therefore, therapy should be initiated with reduced doses, which may be gradually increased during treatment, always under close medical supervision.

In predisposed individuals, prolonged treatment with high doses may lead to dependence, as occurs with other medicines having hypnotic, sedative, and tranquilizing activity.

Elderly patients: In these patients, increased reactivity and higher sensitivity to adverse effects may occur. Therefore, therapy should be initiated with reduced doses, which may be gradually increased under close medical supervision.
Anxiety: Treatment should be as short as possible. Your doctor will monitor you regularly and carefully evaluate the need for continued treatment, especially if you do not have evident symptoms. The total duration of treatment should generally not exceed 8–12 weeks, including a gradual withdrawal period. In certain cases, extension beyond the maximum treatment period may be necessary; in such cases, your doctor will reassess your condition.
Insomnia: Treatment should be as short as possible. The duration of treatment generally ranges from a few days to two weeks, up to a maximum of four weeks, including a gradual withdrawal period. In certain cases, extension beyond the maximum treatment period may be necessary; however, this should not occur without reassessment of the patient's condition.
Take the medicine at bedtime. Do not use Frisium for the treatment of insomnia in individuals under 18 years of age without careful medical evaluation of the actual need.
The single dose for patients under 18 years of age depends on their age, body weight, and general condition.

If you take more Frisium than you should
Do not take a double dose to make up for a missed dose.
In case of accidental ingestion or overdose of Frisium, contact your doctor immediately or go to the nearest hospital.
As with other benzodiazepines, an overdose is generally not life-threatening unless other medicines that depress the Central Nervous System (including alcohol) are taken concomitantly.
Benzodiazepine overdose usually manifests as varying degrees of central nervous system depression, ranging from impaired sensory and mental capacity (drowsiness) to mental confusion and prolonged drowsiness (lethargy).
In more severe cases, symptoms may include loss of muscle coordination (ataxia), decreased muscle strength (hypotonia), low blood pressure (hypotension), respiratory depression, rarely coma, and very rarely death.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody experiences them.

Very common side effects (may affect more than 1 in 10 people)

Drowsiness
Tiredness (asthenia)

Common side effects (may affect up to 1 in 10 people)

Swelling of the face, hands and feet, lips, tongue or throat (Quincke's oedema)
Irritability*
Aggressiveness*
Acute agitation*
Depression (pre-existing depression may be unmasked)
Drug tolerance (especially during prolonged use – see "Warnings and precautions")
Agitation*
Dizziness
Sedation
Attention disturbances
Slurred speech / speech disorders
Distortion of taste (dysgeusia)
Slowing down of physical and mental activities (psychomotor retardation)
Headache (cephalalgia)
Fine tremor of fingers
Loss of muscle coordination (ataxia)
Increased heart rate (tachycardia)
Vomiting
Nausea
Upper abdominal pain
Constipation (stipsis) and dry mouth
Decreased appetite
Itching (pruritus)
Urinary disturbances
Sweating

Uncommon side effects (may affect up to 1 in 100 people)

Memory loss (amnesia) and/or inappropriate behaviour
Confusion
Anxiety*
Delirium*
Nightmares*
Decreased sexual desire
Emotional blunting
Weakening of memory
Reduced ability to memorize new information (anterograde amnesia)
Double vision (diplopia). This disorder occurs particularly at high doses or during long-term treatment and is reversible.
Skin reactions such as rashes (rash)
Weight gain. This reaction occurs particularly at high doses or during long-term treatment and is reversible.
Falls

Rare side effects (may affect up to 1 in 1,000 people)

Allergic reactions (anaphylactic/anaphylactoid reactions)

Side effects with unknown frequency (frequency cannot be estimated from the available data)

Dependence (especially during prolonged use – see "Warnings and precautions")
Difficulty falling asleep or staying asleep*
Rage attacks*
Hallucinations*
Psychotic reactions*
Poor quality of sleep
Suicidal tendencies*
Muscle spasms*
Learning difficulties (cognitive disorders)
Loss of consciousness, after prolonged use of Frisium or medicines of the same class (benzodiazepines), particularly in elderly patients, sometimes associated with respiratory disorders; these effects may sometimes persist for a considerable period of time. Rhythmic, involuntary, oscillating eye movements (nystagmus), particularly at high doses or during long-term treatment
Unsteadiness in gait and other motor functions. These reactions occur particularly at high doses or during long-term treatment and are reversible
Reduced alertness
Fatigue
Dizziness
Respiratory depression, especially at high doses. If you have pre-existing compromised respiratory function (e.g. if you suffer from bronchial asthma) or brain damage, respiratory insufficiency may occur or worsen
Urticaria (hives)
Severe skin diseases: “Stevens-Johnson Syndrome”, “Toxic Epidermal Necrolysis”, manifesting with severe skin and mucous membrane changes, blistering, and general symptoms such as fever, vomiting, diarrhoea. These disorders can be fatal
Muscle weakness
Slowed reaction times
Decreased body temperature (hypothermia)

* These psychiatric disturbances (paradoxical reactions) may occur especially in elderly patients and children. If such reactions occur, discontinue treatment with Frisium.

Adverse reactions of the benzodiazepine class

Dependence
Use of benzodiazepines (even at therapeutic doses) may lead to physical dependence: stopping treatment may result in rebound or withdrawal symptoms (see "Warnings and precautions"). Psychological dependence may also occur. Abuse of benzodiazepines has been reported. Once physical dependence has developed, abrupt discontinuation of treatment may be accompanied by withdrawal symptoms. These may include extreme anxiety, tension, restlessness, confusion, irritability, headache and muscle pain. In severe cases, the following symptoms may occur: feeling detached from reality (derealization), feeling detached from oneself (depersonalization), hallucinations, altered sensitivity (paresthesia) in limbs, hypersensitivity to light, noise and physical contact, hearing disturbances with intolerance to noise (hyperacusis), and epileptic seizures. In the case of benzodiazepines with short duration of action, withdrawal symptoms may become apparent between doses, especially at high doses. This is unlikely to occur with Frisium, as it is not a short-acting benzodiazepine.

Rebound insomnia
Upon discontinuation of treatment, a transient disturbance such as insomnia may occur, which may recur in a worsened form following treatment with benzodiazepines. Since the risk of rebound/withdrawal phenomena is higher after abrupt discontinuation of treatment, the dose should be gradually reduced.

Depression
During use of benzodiazepines, a pre-existing depressive state may be unmasked. Benzodiazepines and related compounds may cause reactions such as: restlessness, irritability, aggressiveness, delirium, anger, nightmares, hallucinations, psychosis, and behavioural changes. Such reactions may be severe. They are more likely in children and elderly patients.

In addition, other side effects have been reported rarely, including yellowing of the skin and eyes (jaundice), increased levels of certain blood tests (bilirubin, liver transaminases, increased alkaline phosphatase), reduction – sometimes severe – in blood cells (thrombocytopenia, agranulocytosis, pancytopenia), a condition called “SIADH” (syndrome of inappropriate antidiuretic hormone secretion), with fluid retention in the body.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report side effects directly via the national reporting system at www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Frisium

Do not store above 25°C.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton after "Exp". The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Frisium contains

The active substance is clobazam. One hard capsule contains 10 mg of clobazam.
The other components are: lactose, maize starch, talc, magnesium stearate. Capsule components: gelatin, titanium dioxide (E 171).

Description of the appearance of Frisium and package contents
Frisium is available as Hard capsules.
Pack: 30 capsules.
Marketing Authorization Holder
Atnahs Pharma Netherlands B.V.
Copenhagen Towers
Ørestads Boulevard 108, 5.tv
DK-2300 Copenhagen S
Denmark
Manufacturer
Opella Healthcare International SAS
56, Route de Choisy
60200 Compiègne (France)
Sanofi S.r.l.
strada statale 17, km 22
67019 Scoppito (AQ)

Friseum