This information is intended for use by health professionals

1. Name of the medicinal product

Welldorm Tablets 707mg

Cloral Betaine 707mg Tablets

2. Qualitative and quantitative composition

Cloral Betaine 707mg Tablets contain 707mg cloral betaine, equivalent to 414mg of chloral hydrate.

3. Pharmaceutical form

Film coated tablets

4. Clinical particulars
4.1 Therapeutic indications

Adults:

Cloral betaine tablets are indictafor the short-term treatment (maximum 2 weeks) of severe insomnia which is interfering with normal daily life and where other therapies (behavioural and pharmacologic) have failed. Cloral betaine tablets should be used As an adjunct to non-pharmacologic therapies.

Adolescents aged 12 years and above:

Cloral betaine tablets are used for the short-term treatment (maximum 2 weeks) of severe insomnia in adolescents with suspected or definite neurodevelopmental disorder, when the insomnia is interfering with normal daily life and other therapies (behavioural and pharmacologic) have failed. Treatment should be as an adjunct to behavioural therapy and sleep hygiene management. The use of cloral betaine tablets and adolescents is not generally recommended and if used should be under the supervision of a medical specialist.

4.2 Posology and method of administration

Conditions for Use:

The treatment should be as short as possible and should not exceed the maximum treatment period of 2 weeks.

Repeat courses of cloral betaine tablets are not recommended and can only be administered following medical specialist re-assessment, since the risk of abuse and dependence increases with the duration of treatment (see section 4.4).

Following prolonged treatment with cloral betaine tablets the dose should be slowly tapered before discontinuation.

The use of Cloral Betaine Tablets in adolescents is not generally recommended and if used should be under the supervision of a medical specialist (see section 4.1).

Posology:

Cloral Betaine Tablets should be administered as a single daily dose, 15-30 minutes before bedtime with water or milk.

Adults

The usual dose is one to two tablets (equivalent to 414 – 828 mg chloral hydrate). Higher doses should not exceed a maximum of 4 tablets (equivalent to 2 g chloral hydrate) per dose.

Elderly population

Dosage as for adults except for the frail elderly or those with hepatic impairment, where a reduction in dose may be appropriate (see section 4.4).

Paediatric population

Adolescents aged 12 years and above:

The adult dose should be taken.

Children between 2 and 11 years:

Cloral Betaine Tablets are not suitable for use in children under 12 years of age; for children between 2 and 11 years, chloral hydrate oral solution isavailable.

Children under 2 years:

Cloral betaine should not be used because the safety and efficacy in children aged under 2 years has not been established (see sections 4.4).

Hepatic impairment:

Cloral Betaine is contraindicated in patients with severe hepatic impairment (see section 4.3). Specific guidelines for dosage adjustments in mild and moderate hepatic impairment are not available; cloral betaine is extensively metabolized by the liver and, therefore, dose adjustments may be warranted.

Renal impairment:

Cloral Betaine is contraindicated in patients with renal failure or severe renal impairment (see section 4.3). Specific guidelines for dosage adjustments in mild and moderate renal impairment are not available; dose adjustments may be warranted.

Method of administration:

Oral use.

4.3 Contraindications

- Hypersensitivity to the active substance, chloral hydrate or to any of the excipients listed in section 6.1,

- in patients with severe hepatic impairment,

- in patients with severe renal impairment,

- in patients with severe cardiac disease,

- in patients with active gastritis, oesophagitis, gastric or duodenal ulcers or perforation,

- in patients susceptible to acute attacks of porphyria.

4.4 Special warnings and precautions for use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2).

Tolerance, dependence, withdrawal, misuse:

Tolerance, dependence and withdrawal symptoms have been reported with cloral betaine. Abrupt discontinuation should not be undertaken in patients receiving prolonged treatment with cloral betaine. Sudden withdrawal of the drug may cause delirium and hallucinations. Slowly withdraw cloral betaine.

Individuals with a history of alcohol or drug abuse or dependence may be at greater risk for abuse and misuse of cloral betaine. Prior to prescribing cloral betaine, each patient's risk for abuse or misuse should be assessed and patients receiving cloral betaine should be monitored for the development of behaviours or conditions of abuse or misuse while on therapy.

Gastrointestinal disorders:

Cloral betaine should be used with caution in patients with history of gastritis, oesophagitis, gastric or duodenal ulceration or perforation. Cloral betaine is contraindicated in patients with active gastritis, oesophagitis, gastric or duodenal ulcers or perforation (see section 4.3).

Hepatic and renal impairment

Cloral betaine should be used with caution in patients with mild to moderate hepatic and renal impairment and is contraindicated in patients with severe hepatic and renal impairment (see sections 4.2 and 4.3).

Elderly patients

Elderly patients are more likely to experience the undesirable effects of hypnotics such as ataxia and confusion which may lead to falls and injury. For use in the frail elderly, it is recommended that the lowest effective dose be administered (see section 4.2 and 4.5).

QT prolongation

Cloral betaine should be used with caution and particular care in patients with low potassium levels, bradyarrhythmia, congenital long QT syndrome and other heart disorders (especially arrhythmia) (see sections 4.5 and 4.8).

4.5 Interaction with other medicinal products and other forms of interaction

No formal assessments of pharmacokinetic interactions between chloral hydrate and other therapeutic medicinal products have been conducted.

Concomitant use of alcohol and cloral betaine may potentiate the sedative effect; concomitant use should be avoided.

In combination with CNS depressants an enhancement of the central depressive effect may occur. Concomitant use with antipsychotics, hypnotics, anxiolytics/sedatives, antidepressant agents, centrally acting muscle relaxants, narcotic analgesics, anti-epileptic drugs, anaesthetics and sedative antihistamines should be avoided.

The concomitant use of drugs that also prolong the QT interval in ECG (for example, antiarrhythmics of Class IA or III, antibiotics, agents against malaria, H1 antihistamines, antipsychotics or medicinal products known to cause hypokalaemia or hypomagnesaemia) can lead to cardiac arrhythmias (see sections 4.4 and 4.8).

Chloral hydrate followed by intravenous furosemide may result in sweating, hot flushes and variable blood pressure including hypertension due to a hypermetabolic state caused by displacement of thyroid hormone from its bound state.

Delirium may occur, especially in the elderly, particularly when used in conjunction with psychotropics or anticholinergics.

In patients taking anticoagulants, when chloral hydrate is added to or withdrawn from the drug regimen, or its dosage changed, careful monitoring of the prothrombin time is required.

Chloral hydrate may interfere with laboratory tests of thyroid function.

4.6 Fertility, pregnancy and lactation

Cloral Betaine Tablets should not be used in pregnancy and lactation.

Pregnancy

Little information is available on the possible adverse effects of chloral hydrate on human pregnancy. Chloral hydrate is known to cross the human placenta at term, but its use during relatively few pregnancies did not cause a detectable increase in abnormal outcomes. Some data suggest that prolonged administration of sedative doses of cloral betaine to neonates increases the likelihood of hyperbilirubinemia.

Breast Feeding

Low levels of chloral hydrate have been found in breast milk. Although breastfeeding infants may be sedated by chloral hydrate in breast milk, the highest concentration measured in the milk (about 15 µg/ml) was considerably lower than that which would be measured in blood at a clinically active dose (100 µg/ml).

Fertility

There is no information relating to the effects of Cloral Betaine Tablets 707mg on fertility.

4.7 Effects on ability to drive and use machines

Patients receiving Cloral Betaine Tablets should be warned that their ability to drive or use machinery may be impaired by drowsiness.

4.8 Undesirable effects

The adverse reactions presented in the below table have been reported. The frequency grouping is defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

System Organ Class

Frequency and Adverse Reaction

Immune system disorders:

Not known: hypersensitivity, allergic skin reactions

Metabolism and nutrition disorders:

Not known: ketonuria

Psychiatric disorders:

Not known: anxiety, hyperactivity, confusion, tolerance, dependence, delirium, abuse, chronic intoxication, withdrawal symptoms

Nervous system disorders:

Not known: headache, ataxia

Respiratory, thoracic and mediastinal disorders:

Not known: dyspnoea, respiratory depression

Cardiac disorders:

Not known: QTc prolongation, arrhythmias (see sections 4.4 and 4.5)

Gastrointestinal disorders:

Not known: gastric irritation, abdominal distension, flatulence, gastric necrosis, gastric perforation, nausea, vomiting, gastritis

Renal and urinary disorders:

Not known: parenchymatous renal injury

Elderly patients:

Ataxia, confusion, falls and injuries.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms:

The signs and symptoms of overdose involve the cardiovascular, respiratory and central nervous systems. These may include respiratory depression, arrhythmias, hypothermia, pin-point pupils, hypotension or coma.

Gastric irritation may result in vomiting and even gastric necrosis. If the patient survives, icterus due to hepatic damage and albuminuria from renal damage may appear.

Serious problems have arisen with doses as little as 4g and l0g can be fatal.

Management:

Overdosage should be treated with gastric lavage or inducing vomiting to empty the stomach. Supportive measures must be used.

Haemodialysis, and in some cases haemoperfusion, have been reported to be effective in promoting the clearance of trichloroethanol.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and Sedatives, ATC code: N05CC01

Cloral Betaine Tablets are a derivative of chloral hydrate, which leads to a decrease in sleep latency and in the number of awakenings. A near natural sleep is induced and the REM/Non-REM ratio is not altered.

Mechanism of action:

The metabolite (trichloroethanol) is responsible for the pharmacological effect. The proposed mechanisms for the depression of the central nervous system include potentiating the function of GABAA receptors, inhibition of excitatory amino acid-activated currents mediated by N-methyl-D-aspartate, and allosteric modulation of the 5- hydroxytryptamine 3 receptor-mediated depolarization of the vagus nerve.

5.2 Pharmacokinetic properties

Absorption:

Cloral betaine completely dissociates in solution to give chloral hydrate and trimethylglycine (betaine). Chloral hydrate is rapidly absorbed from the gastrointestinal tract and starts to act within 30 minutes of oral administration. The duration of action is for between 4 to 8 hours. Plasma concentrations of chloral hydrate (or the major metabolite trichloroethanol) required for sedative or hypnotic effects are unknown.

Distribution:

Chloral hydrate is widely distributed throughout the body, as is the active metabolite trichloroethanol. Both have been detected in the CSF, umbilical cord blood, foetal blood and amniotic fluid. The active metabolite is 70% to 80% protein bound. Following therapeutic doses of chloral hydrate, only small amounts of the clinically active metabolite is distributed into breast milk.

Metabolism:

Chloral hydrate is rapidly metabolised by the liver, erythrocytes, and other tissues to form trichloroethanol (an active metabolite). The reduction of chloral hydrate to trichloroethanol is catalysed by alcohol dehydrogenase and other enzymes. The plasma half-life of trichloroethanol is about 4 to 12 hours. This is increased to between 1 to 2 days in neonates. A small but variable amount of chloral hydrate and a larger portion of trichloroethanol are oxidised to trichloroacetic acid (an inactive metabolite) in the liver and kidneys. Trichloroethanol may also be conjugated to form trichloroethanol glucuronide, another inactive metabolite.

Other metabolites of chloral hydrate such as trichloroacetic acid and dichloroacetate are inactive metabolites, and produced in small quantities which are not anticipated to produce any safety concerns during short-term use.

Excretion:

The metabolites of chloral hydrate are slowly excreted in the urine. Some metabolites may also be excreted into the bile and faeces. Chloral hydrate is not excreted in the urine unchanged. The quantities of metabolites excreted in the urine may vary between individuals, as well as in the same individual on different days.

5.3 Preclinical safety data

Chloral hydrate induces liver tumours in male mice, with no tumourigenic effects in rats. The mechanism of tumour induction is not known, but in the absence of clear evidence of mutagenic and clastogenic potential, it is unlikely to be relevant in man.

There are no controlled studies on toxicity to humans following extended exposure to chloral hydrate. Studies in laboratory animals demonstrate that liver is a target tissue and hepatocellular tumours have been observed in male mice and adenomas in the pituitary gland pars distalis in female mice after chronic, high-dose administration. No tumours occurred in rats after chronic high-dose administration. Slight effects are also observed in some studies in laboratory animals on sperm motility, developmental neurotoxicity (passive avoidance learning), and humoral immunity. All of the adverse effects noted in studies in laboratory animals occur at an exposure that is greater than the recommended clinical dose for sedation in humans.

Chloral hydrate did not cause meiotic delay in the oocytes of adult mice when administered at the time of resumption of maturation induced by hormones. It did cause adverse effects in vitro when a synchronized population of oocytes was exposed prior to resumption of maturation.

There was a slight depression in humoral and cell-mediated immunity in female CD1 mice exposed for 90 days to chloral hydrate in the drinking water. However, other data on haemagglutination titre and survival in chronic rodent bioassays indicate that immunosuppressive effects are unlikely.

6. Pharmaceutical particulars
6.1 List of excipients

In addition to the active ingredient, Cloral Betaine Tablets contain:

Povidone

BP

Maize starch

Ph. Eur.

Sodium citrate

BP

Purified talc

Ph. Eur.

Magnesium stearate

Ph. Eur.

Hypromellose

Ph. Eur.

Hydroxypropyl cellulose

Ph. Eur.

Polyethylene glycol

Ph. Eur.

Disodium edatate

Ph. Eur.

Cannoisine lake (E122)

USE

Titanium dioxide (El71)

BP

Brilliant blue FCF aluminium lake (E133)

BP

6.2 Incompatibilities

None known

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C.

Do not refrigerate.

Store in the original package.

6.5 Nature and contents of container

Aluminium foil topped opaque PVC-PVdC blister packs each containing 4, 14 or 15 Cloral Betaine Tablets, presented in a carton - pack sizes 4, 28, 30, or 56

6.6 Special precautions for disposal and other handling

No special requirements

7. Marketing authorisation holder

Marlborough Pharmaceuticals Ltd,

Sovereign House, Miles Gray Road,

Basildon, Essex SS14 3FR, UK

8. Marketing authorisation number(s)

PL 23138/0015

9. Date of first authorisation/renewal of the authorisation

10 August 2004

10. Date of revision of the text

July 2021