COLMIFEN Tablet Ref.[28172] Active ingredients: Baclofen

Psychiatric and nervous system disorders

Porphyria, history of alcoholism, hypertension, psychotic disorders, schizophrenia, depressive or manic disorders, confusional states or Parkinson’s disease may be exacerbated by treatment with Colmifen. Patients suffering from these conditions should therefore be treated cautiously and kept under close surveillance.

Suicide and suicide-related events have been reported in patients treated with baclofen. In most cases, the patients had additional risk factors associated with an increased risk of suicide including alcohol use disorder, depression and/or a history of previous suicide attempts. Close supervision of patients with additional risk factors for suicide should accompany drug therapy. Patients (and caregivers of patients) should be alerted about the need to monitor for clinical worsening, suicidal behaviour or thoughts or unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Cases of misuse, abuse and dependence have been reported with baclofen. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of baclofen misuse, abuse or dependence e.g. dose escalation, drug-seeking behaviour, development of tolerance.

Epilepsy

Colmifen may also exacerbate epileptic manifestations but can be employed provided appropriate supervision and adequate anticonvulsive therapy are maintained.

Others

Colmifen should be used with extreme care in patients already receiving antihypertensive therapy, (see section 4.5).

Colmifen should be used with caution in patients suffering from cerebrovascular accidents or from respiratory and hepatic impairment.

Since unwanted effects are more likely to occur, a cautious dosage schedule should be adopted in elderly and patients with spasticity of cerebral origin (see section 4.2).

Renal impairment

Signs of overdose have been observed in patients with renal impairment taking oral Colmifen at doses of more than 5 mg per day. Colmifen should be used with caution in patients with renal insufficiency and should be administered to patients with end-stage renal failure (CKD stage 5, GFR < 15mL/min) only if the expected benefit outweighs the potential risk (see section 4.2). Neurological signs and symptoms of overdose including clinical manifestations of toxic encephalopathy (e.g. confusion, disorientation, somnolence and depressed level of consciousness) have been observed in patients with renal impairment taking oral baclofen at doses of more than 5 mg per day and at doses of 5 mg per day in patients with end-stage failure being treated with chronic haemodialysis. Patients with impaired renal function should be closely monitored for prompt diagnosis of early symptoms of toxicity (see section 4.9 Overdose).

Cases of baclofen toxicity have been reported in patients with acute renal failure (see section 4.9).

Particular caution is required when combining Colmifen to drugs or medicinal products that can significantly affect renal function. Renal function should be closely monitored and Colmifen daily dosage adjusted accordingly to prevent baclofen toxicity.

Besides discontinuing treatment, unscheduled haemodialysis might be considered as a treatment alternative in patients with severe baclofen toxicity. Haemodialysis effectively removes baclofen from the body, alleviates clinical symptoms of overdose and shortens the recovery time in these patients.

Urinary disorders

Under treatment with Colmifen neurogenic disturbances affecting emptying of the bladder may show an improvement. In patients with pre-existing sphincter hypertonia, acute retention of urine may occur; the drug should be used with caution in such cases.

Laboratory tests

In rare instances elevated aspartate aminotransferase, blood alkaline phosphatase and blood glucose levels in serum have been recorded. Appropriate laboratory tests should be performed in patients with liver diseases or diabetes mellitus in order to ensure that no drug induced changes in these underlying diseases have occurred.

Abrupt withdrawal

Anxiety and confusional state, delirium, hallucination, psychotic disorder, mania or paranoia, convulsion (status epilepticus), dyskinesia, tachycardia, hyperthermia, rhabdomyolysis and – as rebound phenomenon – temporary aggravation of spasticity have been reported with abrupt withdrawal of Colmifen especially after long term medication.

Neonatal convulsions have been reported after intrauterine exposure to oral Colmifen (see section 4.6).

Treatment should always, (unless serious adverse effects occur), be gradually discontinued by successively reducing the dosage over a period of about 1-2 weeks.

Paediatric patients

There is very limited clinical data on the use of Colmifen in children under the age of one

year. Use in this patient population should be based on the physician’s consideration of individual benefit and risk of therapy.

Posture and balance

Colmifen should be used with caution when spasticity is needed to sustain upright posture and balance in locomotion (see section 4.2).

Levodopa/dopa decarboxylase (DDC) inhibitor (Carbidopa)

In patients with Parkinson’s disease receiving treatment with Colmifen and levodopa (alone or in combination with DDC inhibitor, carbidopa), there have been reports of mental confusion, hallucinations, nausea and agitation. Worsening of the symptoms of Parkinsonism has also been reported. Hence, caution should be exercised during concommitant administration of Colmifen and levodopa/carbidopa.

Drugs causing Central Nervous System (CNS) depression

Increased sedation may occur when Colmifen is taken concomitantly with other drugs causing CNS depression including other muscle relaxants (such as tizanidine), with synthetic opiates or with alcohol (see section 4.7).

The risk of respiratory depression is also increased. In addition, hypotension has been reported with concomitant use of morphine and intrathecal baclofen. Careful monitoring of respiratory and cardiovascular functions is essential especially in patients with cardiopulmonary disease and respiratory muscle weakness.

Antidepressants

During concomitant treatment with tricyclic antidepressants, the effect of Colmifen may be potentiated, resulting in pronounced muscular hypotonia.

Lithium

Concomitant use of oral Colmifen and lithium resulted in aggravated hyperkinetic symptoms. Thus, caution should be exercised when Colmifen is used concomitantly with lithium.

Antihypertensives

Since concomitant treatment with Colmifen and anti-hypertensives is likely to increase the fall in blood pressure, the dosage of antihypertensive medication should be adjusted accordingly.

Agents reducing renal function

Drugs or medicinal products that can significantly affect renal function may reduce baclofen excretion leading to toxic effects (see section 4.4).

Pregnancy

During pregnancy, especially in the first 3 months, Colmifen should only be employed if its use is of vital necessity. The benefits of the treatment for the mother must be carefully weighed against the possible risks for the child. Baclofen crosses the placental barrier.

One case of suspected withdrawal reaction (generalised convulsions) has been reported in a week-old infant whose mother had taken oral baclofen 80 mg daily throughout her pregnancy. The convulsions, which were refractory to standard anticonvulsant treatment, ceased within 30 minutes of giving baclofen to the infant.

Breast-feeding

In mothers taking Colmifen in therapeutic doses, the active substance passes into the breast milk, but in quantities so small that no undesirable effects on the infant are to be expected.

Colmifen may be associated with adverse effects such as sedation, dizziness, somnolence and visual impairment (See section 4.8) which may impair the patient’s reaction. Patients experiencing these adverse reactions should be advised to refrain from driving or using machines.

Adverse effects occur mainly at the start of treatment (e.g. sedation, somnolence and nausea), if the dosage is raised too rapidly, if large doses are employed, or in elderly patients. They are often transitory and can be attenuated or eliminated by reducing the dosage; they are seldom severe enough to necessitate withdrawal of the medication.

Should nausea persist following a reduction in dosage, it is recommended that Colmifen be ingested with food or a milk beverage.

In patients with a history of psychiatric illness or with cerebrovascular disorders (e.g. stroke) as well as in elderly patients, adverse reactions may assume a more serious form.

Lowering of the convulsion threshold and convulsions may occur, particularly in epileptic patients.

Certain patients have shown increased spasticity as a paradoxical reaction to the medication.

An undesirable degree of muscular hypotonia – making it more difficult for patients to walk or fend for themselves – may occur and can usually be relieved by re-adjusting the dosage (i.e. by reducing the doses given during the day and possibly increasing the evening dose).

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to 1/100); rare (≥1/10000 to 1/1000) very rare (<1/10000) and Not known (cannot be estimated from the available data).

Table 1. Tabulated summary of adverse drug reactions:

^* Cases of central sleep apnoea syndrome have been observed with baclofen at high doses (≥100 mg) in patients who are alcohol dependent.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 national reporting system: Cyprus, Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Fax: +357 22608649, Website: www.moh.gov.cy/phs.

Not applicable.