GovWire

MDR number

MDR 008-11/23

Company name

Atnahs Pharma UK Limited

Product name

Clobazam Atnahs 5mg/5ml Oral Suspension, PL 43252/0010

SNOMED Code

37471711000001108

Active Pharmaceutical Ingredient: Clobazam

Product name

Clobazam Atnahs 10mg/5ml Oral Suspension, PL 43252/0011

SNOMED Code

37471111000001107

Active Pharmaceutical Ingredient: Clobazam

Brief description of the problem

Atnahs Pharma UK Ltd has informed the MHRA that the batches of Clobazam Atnahs 5mg/5ml and 10mg/5ml Oral Suspension listed in this notification do not contain the most up to date safety information. The Summary of Product Characteristics (SmPC) and the Patient Information Leaflets (PIL) present in the pack are missing significant information. This is in relation to the use of the product in children (contraindicated), pregnancy, depression, drug dependence, numerous interactions and adverse effects which are missing from the PIL present in the pack and in the SmPC.

Please see below for an extract of the key information that was missing in the leaflets packed in the batches affected. Healthcare professionals and patients should note that the full details for information missing in the SmPC and in the PIL for these batches are listed in the appendices within this notification, available in the download document.

Healthcare professionals should note that the information in the PIL and SmPC has already been updated and the relevant links can be found in the following sections of this notification.

Summary of key missing information from the SmPC

Section 4.3

As there is no age appropriate formulation to enable safe and accurate dosing, no dosage recommendations can be made in children under 6 years of age (see section 4.2)

Section 4.4

Depression and personality disorders Some epidemiological studies suggest an increased incidence of suicidal ideation, suicide attempt and suicide in patients with or without depression, and treated with benzodiazepines and other hypnotics, including clobazam. However, a causal relationship has not been established (see section 4.8).

Dependence These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur; derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

Risks from concomitant use of opioids and benzodiazepinesConcomitant use of Clobazam and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as Clobazam with opioids should be reserved for patients for whom alternative treatment options are not possible.If a decision is made to prescribe Clobazam concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2). The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their environment to be aware of these symptoms (see section 4.5)

Section 4.5

OpioidsThe concomitant use of sedative medicines such as benzodiazepines or related drugs such as Clobazam with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4)

CannabidiolWhen cannabidiol and clobazam are co-administered, bi-directional PK interactions occur. Based on a healthy volunteer study, elevated levels (3- to 4-fold) of N-desmethylclobazam (an active metabolite of clobazam) can occur when combined with cannabidiol, likely mediated by CYP2C19 inhibition.Increased systemic levels of these active substances may lead to enhanced pharmacological effects and to an increase in adverse drug reactions.

Concomitant use of cannabidiol and clobazam increases the incidence of somnolence and sedation. Reduction in dose of clobazam should be considered if somnolence or sedation are experienced when clobazam is co-administered with cannabidiol.

Section 4.6

Pregnancy Nevertheless, a large amount of data collected from cohort studies has not demonstrated evidence of the occurrence of major malformations following exposure to benzodiazepines during the first trimester of pregnancy, although incidences of cleft lip and palate were reported in certain case-control studies.

Clobazam is not recommended during pregnancy and in women of childbearing potential not using contraception. Clobazam crosses the placenta. Animal studies have demonstrated reproductive toxicity (see section 5.3). Women of childbearing potential should be informed of the risks and benefits of the use of clobazam during pregnancy. Women of childbearing potential should be informed to contact her physician regarding discontinuation of the product if they are pregnant or intend to become pregnant. If clobazam treatment is continued, it should be used at the lowest effective dose. Cases of reduced fetal movement and fetal heart rate variability have been described after administration of benzodiazepines during childbirth, effects on the neonate, such as respiratory depression (including respiratory distress and apnea), sedation signs, hypothermia, hypotonia, and feeding difficulties in the newborn (so-called floppy infant syndrome) are to be expected

Section 4.8

The following significant side effects were not included in the PIL (in order of frequency): * Common side effects: depression, drug tolerance* Uncommon side effects: anxiety, delusion, memory impairment, amnesia (including anterograde amnesia)* Not known (frequency cannot be estimated from available data): dependence, psychotic disorder, suicidal ideation, hallucinations, cognitive disorder, respiratory depression & failure, Steven Johnsons Syndrome, toxic epidermal necrolysis, hypothermia

Advice for healthcare professionals

There is no risk to product quality because of this issue, therefore the affected batches are not being recalled. Healthcare professionals are advised to check if patients belong to any of the groups at risk and provide advice accordingly or do not prescribe and/or dispense this product. Where appropriate, healthcare professionals should provide a copy of the PIL when supplying any remaining stock to patients.

A copy of the correct SmPC and PIL can be found in the following links:

• SmPC Clobazam Atnahs 5mg/5ml Oral Suspension: https://www.medicines.org.uk/emc/product/721/smpc

• SmPC Clobazam Atnahs 10mg/5ml Oral Suspension: https://www.medicines.org.uk/emc/product/7618/smpc

• PIL Clobazam Atnahs 5mg/5ml &10mg/5ml Oral Suspension: https://www.medicines.org.uk/emc/files/pil.7618.pdf

Atnahs Pharma UK Ltd has also confirmed that all remaining packs of the impacted batches will not be distributed and that all future batches will contain the updated PIL. Upon request, the manufacturer will post hard copies of the updated PIL to wholesalers and pharmacies so that any remaining stock in the dispensary can be supplemented with the correct PIL information from the end of Jan 2024.

Advice for patients

This issue is about missing information on the Patient Information Leaflets (PILs) and Summary of Product Characteristics (SmPC). The medicine itself is not affected and therefore patients do not need to take any specific action relating to the product. If you have any

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