Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

Sexual dysfunction
Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI.
Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide- related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Paediatric population
Use in children and adolescents under 18 years of age
Milnacipran should not be used in the treatment of children and adolescents under the age of 18 years.
Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with a placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Serotonin syndrome
As with other serotoninergic agents, the development of a potentially life-threatening serotonin syndrome may occur with milnacipran treatment, particularly with concomitant use of other medicines that may affect the serotonergic neurotransmitter system (as irreversible MAO inhibitors (iproniazide), A selective MAO inhibitors (linezolid, moclobemide methylene blue), St. John’s Wort [Hypericum perforatum], pethidine, tramadol, most of the antidepressant (see sections 4.3 and 4.5)).

Serotonin syndrome symptoms may include:
- Digestive symptoms (diarrhoea),
- Changes in psychiatric status and behaviour (agitation, confusion, hypomania), 

-   Motor dysfunction (tremor, rigidity, myoclonus, hyperreflexia and ataxia), -   Autonomic instability (labile blood pressure, tachycardia, shivering, hyperthermia, possibly coma).

The concomitant use of milnacipran with alpha and beta sympathomimetics (IM and IV routes) is not recommended.

Precautions for Use

Patients with insomnia or nervousness at the beginning of treatment may require transient symptomatic therapy.

If a patient experiences a switch into frank mania, treatment with Milnacipran should be discontinued and in most cases a sedative antipsychotic agent prescribed.
Miln-Avnir should be discontinued in patients who develop jaundice or other evidence of liver dysfunction. Treatment with Miln-Avnir should not be resumed unless another cause can be established. Although no interaction with alcohol has been evidenced, it is recommended to avoid alcohol intake, just as with any psychotropic medication.
Systemic body exposure to Milnacipran is increased by 20% when combined with levomepromazine, in healthy volunteers. A higher increase may be suspected in elderly or renal impairment patients if the drugs are to be combined.

Milnacipran should be prescribed with caution in the following cases: 
-   in patients with renal failure:
Dosage may have to be reduced because of prolongation of elimination half-life (see section         4.2);
-   in patients with a history of difficult passage of urine, notably in patients with prostatic hypertrophy and other genito-urinary disorders. Because of the noradrenergic component of the mechanism of Milnacipran action, a monitoring of the miction disorders is necessary; -   in patients with hypertension or cardiac disease:
Blood pressure and heart rate monitoring is recommended at treatment initiation, following dosage increases and periodically throughout the treatment with milnacipran for all patients and more closely in patients with known cardiovascular risk. In case of sustained elevated blood pressure or elevated heart rate, discontinuation of the treatment with milnacipran should be considered if clinically warranted.
-   in patients with high intra-ocular pressure or at risk of narrow-angle glaucoma; -   in patients with epilepsy or with a history of epilepsy: Milnacipran should be used with caution and should be discontinued in any patient developing a seizure.

There have been cases of hyponatraemia in patients receiving serotonin re-uptake inhibitors, possibly due to the syndrome of inappropriate antidiuretic hormone secretion. Caution is advised in elderly, patients taking diuretics or other treatment known to induce hyponatremia, patients with cirrhosis or malnutrition.
Cases of haemorrhages, sometimes serious, have been reported with the use of serotonin re-uptake inhibitors. SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6, 4.8).
Caution should be exercised in patients concomitantly treated with oral anticoagulants, drugs which have an effect on platelet function, e.g. NSAIDs and aspirin, or other drugs that may increase the risk of bleeding. Caution is also required in patients with previous bleeding  abnormalities.

The safety and efficacy of milnacipran for treatment of major depressive episodes in adults in higher dosage than 100 mg per day have not been established. For patients who do not experience clinical benefit with 100 mg per day, the treatment should be discontinued.

Discontinuation of treatment
The risk of withdrawal reactions seen with SSRI’s and SNRI’s may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction.
Generally, the symptoms are mild to moderate; however, in some patients, they may be severe in intensity. They usually occur within the first few days of discontinuing treatment but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose.
Generally, these symptoms are self-limiting and resolve within two weeks, though in some individuals they may be prolonged (2-3 months or more).

It is therefore advised that milnacipran should be gradually tapered when discontinuing treatment and not abruptly discontinued after extended use (see section 4.2 and 4.8).

Effects on Driving

4.7 Effects on ability to drive and use machines

Although no alteration in cognitive or psychomotor functions has been observed in healthy volunteers, this medication can reduce mental and physical capacities necessary to perform certain dangerous tasks, such as operating machinery or driving motor vehicles.