Methylphenidate

Caution is advised in patients being treated with methylphenidate with any other medicinal product that can also elevate blood pressure.

Because of possible hypertensive crisis, methylphenidate is contraindicated in patients being treated (currently or within the preceding two weeks) with MAO inhibitors.

It is not known how methylphenidate may affect plasma concentrations of concomitantly administered medicinal products. Therefore, caution is recommended at combining methylphenidate with other medicinal products, especially those with narrow therapeutic window.

Serious adverse reactions, including sudden death, have been reported in concomitant use with clonidine. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systematically evaluated.

Methylphenidate has not been studied in patients with hepatic impairment. Caution should be exercised in these patients.

Methylphenidate has not been studied in patients with renal impairment. Caution should be exercised in these patients.

Alcohol may exacerbate the adverse reactions in CNS with psychoactive medicinal products, including methylphenidate. It is therefore advisable for patients to abstain from alcohol during treatment.

There are reports indicating that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primodone), and some antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors). When starting and stopping treatment with methylphenidate, it may be necessary to adjust the dose of these medicinal products already being taken and establish drug plasma concentrations (or for coumarin, coagulation times).

Methylphenidate may decrease the effectiveness of medicinal products used to treat hypertension.

There is a risk of sudden blood pressure and heart rate increase during surgery. If surgery is planned, methylphenidate treatment should not be used on the day of surgery.

Caution is recommended when administering methylphenidate with dopaminergic medicinal products, including antipsychotics. Because a predominant action of methylphenidate is to increase extracellular dopamine levels, methylphenidate may be associated with pharmacodynamic interactions when co-administered with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants) or with dopamine antagonists including antipsychotics.

Sudden death has been reported in association with the use of stimulants of the central nervous system (CNS) at usual doses in children and adolescents, some of whom had structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone may carry an increased risk of sudden death, stimulant medicinal products are not recommended in children or adolescents with known cardiac structural abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant medicinal product.

Particular care should be taken in using methylphenidate to treat ADHD in patients with comorbid bipolar disorder (including untreated type 1 bipolar disorder or other forms of bipolar disorder) because of concern for possible precipitation of a mixed/manic episode in such patients. Prior to initiating treatment with methylphenidate, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Close ongoing monitoring is essential in these patients. Patients should be monitored for symptoms at every adjustment of dose, then at least every 6 months and at every visit.

Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant products. In the case of emergent psychiatric symptoms or exacerbation of pre-existing psychiatric disorders, methylphenidate should not be given unless the benefits outweigh the risks to the patient.

Development of de novo or worsening of pre-existing psychiatric disorders should be monitored at every adjustment of dose, then at least every 6 months, and at every visit; discontinuation of treatment may be appropriate.

Methylphenidate should be used with caution in patients with epilepsy. Methylphenidate may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and rarely in patients without a history of convulsions and no EEG abnormalities. If seizure frequency increases or new-onset seizures occur, methylphenidate should be discontinued.

Data from a cohort study of in total approximately 3 400 pregnancies exposed in the first trimester do not suggest an increased risk of overall birth defects. There was a small increased occurrence of cardiac malformations (pooled adjusted relative risk, 1.3; 95% CI, 1.0-1.6) corresponding to 3 additional infants born with congenital cardiac malformations for every 1 000 women who received methylphenidate during the first trimester of pregnancy, compared with non-exposed pregnancies. Cases of neonatal cardiorespiratory toxicity, specifically foetal tachycardia and respiratory distress have been reported in spontaneous reports.

Animal studies have shown reproductive toxicity at maternally toxic doses.

Methylphenidate should not be used during pregnancy unless a clinical decision is made that postponing treatment may pose a greater risk to the pregnancy.

Methylphenidate has been detected in breast milk of women treated with methylphenidate.

There is one case report of an infant who experienced an unspecified decrease in weight during the period of exposure but recovered and gained weight after the mother discontinued treatment with methylphenidate.

A risk to the newborn/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from methylphenidate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of methylphenidate on fertility are available.

Methylphenidate did not impair fertility in male or female mice.

No clinically relevant effects on fertility were observed in animal studies.

Methylphenidate has moderate influence on the ability to drive and use machines. It can cause dizziness, drowsiness and visual disturbances, including difficulties with accommodation, diplopia and blurred vision. Patients should be warned of these adverse reactions and advised that if affected, they should avoid potentially hazardous activities such as driving or operating machines.

Summary of the safety profile

In general, the most common adverse reactions associated with methylphenidate treatment have been reported with a very common frequency are decreased appetite, insomnia, nervousness, headache, nausea and dry mouth.

Tabulated list of adverse reactions

The table below shows all adverse reactions reported during clinical trials and post-marketing experience with methylphenidate, as well as those adverse reactions which have been reported with other methylphenidate hydrochloride formulations. If adverse reactions frequencies reported with methylphenidate and other methylphenidate hydrochloride formulations were different, the highest frequency from the safety databases was used.

Adverse reactions are listed by MedDRA system organ class and frequency convention as follows: 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 available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions:

^** Adverse reactions from clinical trials in adult patients that were reported with a higher frequency than in children and adolescents.
^*** Reports were poorly documented and in most cases, patients were also receiving other medicinal products, so the role of methylphenidate is unclear
^**** These usually occur at the beginning of treatment and may be alleviated by concomitant food intake
^***** Cases of abuse and dependence have been described, more often with immediate release formulations.
^****** Frequency derived from adult clinical trials and not on data from trials in children and adolescents; may also be relevant for children and adolescents

Description of selected adverse reactions

Very rare cases of sudden death have been also reported in association with the use of stimulants of the CNS at usual doses in children, some of whom had structural cardiac abnormalities or other serious heart problems. Cardiovascular status should be carefully assessed and monitored.