Selegiline

Mechanism

Selegiline selectively inhibits monoamine oxidase type B (MAO-B), the enzyme mainly responsible for dopamine breakdown in the brain (selegiline SmPC). The US Food and Drug Administration (FDA) label for selegiline in Parkinson's disease adds that this inhibition is irreversible, that selectivity for MAO-B may be incomplete even at the recommended dose, and that it is lost above it (selegiline SmPC: above 10 mg a day). Amitriptyline is a tricyclic antidepressant that blocks the reuptake of noradrenaline and serotonin at nerve endings (amitriptyline SmPC). With breakdown slowed and reuptake blocked, serotonin builds up in the synapse. The selegiline SmPC reports severe central nervous system toxicity, a serotonin syndrome, sometimes with hypertension, hypotension and sweating, in patients on tricyclic antidepressants plus selegiline. On that basis it contraindicates the combination. The FDA amitriptyline label reports hyperpyretic crises, severe convulsions and deaths in patients given a tricyclic antidepressant together with an MAO inhibitor.

Symptoms

Serotonin syndrome: agitation, confusion, hallucinations, delirium up to coma, tremor, myoclonus, muscle rigidity, hyperreflexia, incoordination, hyperthermia, tachycardia, labile blood pressure, sweating, nausea, vomiting, diarrhoea (amitriptyline and selegiline SmPCs). With tricyclic antidepressants the selegiline SmPC describes severe central nervous system toxicity with hypertension, hypotension and sweating. The US Food and Drug Administration (FDA) amitriptyline label warns of hyperpyretic crises, severe convulsions and deaths when a tricyclic antidepressant and a monoamine oxidase (MAO) inhibitor are taken together.

Management

The combination is contraindicated. The selegiline SmPC bans selegiline with tricyclic antidepressants (sections 4.3 and 4.5). The amitriptyline SmPC bans amitriptyline with monoamine oxidase (MAO) inhibitors and names selegiline (sections 4.3 and 4.5). The US Food and Drug Administration (FDA) amitriptyline label bans MAO inhibitors as a class. The two drugs are not given together at any dose or for any length of time. When switching from selegiline to amitriptyline, allow at least 14 days after the last dose of selegiline (FDA amitriptyline label; FDA label for selegiline in Parkinson's disease). Start amitriptyline cautiously, with gradual dose increases (FDA amitriptyline label). When switching from amitriptyline to selegiline, allow 14 days after stopping amitriptyline (amitriptyline SmPC). If a patient is already taking both, stop both immediately at the first signs of serotonin syndrome and start supportive treatment (FDA amitriptyline label). When the syndrome is suspected, the amitriptyline SmPC asks for a dose reduction or interruption depending on severity. The FDA label for the selegiline patch names only clomipramine and imipramine among tricyclics, but the oral selegiline and amitriptyline documents ban the whole class.

Mechanism

Selegiline selectively inhibits monoamine oxidase type B (MAO-B), the enzyme mainly responsible for dopamine breakdown in the brain (selegiline SmPC). The US Food and Drug Administration (FDA) label for selegiline in Parkinson's disease adds that this inhibition is irreversible, that selectivity for MAO-B may be incomplete even at the recommended dose, and that it is lost above it (selegiline SmPC: above 10 mg a day). Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). Both fluoxetine and its active metabolite norfluoxetine have a very long elimination half-life (selegiline and fluoxetine SmPCs). With serotonin breakdown slowed and reuptake blocked, serotonin builds up in the synapse. The selegiline SmPC contraindicates the combination with SSRIs because of the risk of serotonin syndrome and names fluoxetine. The FDA label for the selegiline patch reports serious, sometimes fatal central nervous system toxicity when nonselective MAO inhibitors are combined with serotonergic drugs. The FDA label for selegiline in Parkinson's disease reports fatal and non-fatal cases of serotonin syndrome in patients treated with antidepressants together with selegiline. Because fluoxetine is cleared so slowly, the risk persists for weeks after it is stopped. That is why the documents require a 5-week gap before selegiline is started.

Symptoms

For the combination with selective serotonin reuptake inhibitors (SSRIs), the selegiline SmPC lists confusion, hypomania, hallucinations and manic episodes, agitation, myoclonus, hyperreflexia, incoordination, shivering, tremor, seizures, ataxia, sweating, diarrhoea, fever and hypertension. All of these can be part of serotonin syndrome. The fluoxetine SmPC describes the reaction with a monoamine oxidase (MAO) inhibitor as hyperthermia, rigidity, myoclonus, autonomic instability with rapid swings in vital signs, and mental changes ranging from confusion and irritability to extreme agitation, delirium and coma. The US Food and Drug Administration (FDA) label for the selegiline patch adds tachycardia, labile blood pressure, nausea and vomiting.

Management

The combination is contraindicated. The selegiline SmPC names fluoxetine among the drugs selegiline must not be used with (section 4.3) and bans selegiline with all selective serotonin reuptake inhibitors (SSRIs) (section 4.5). The US Food and Drug Administration (FDA) label for the selegiline patch contraindicates fluoxetine (section 4). The FDA fluoxetine label contraindicates monoamine oxidase (MAO) inhibitors intended to treat psychiatric disorders (section 4.1). The fluoxetine SmPC itself only asks for caution and closer follow-up with selegiline, but the stricter documents take precedence. When switching from selegiline to fluoxetine, allow at least 14 days after stopping selegiline (selegiline SmPC, section 4.5; FDA label for selegiline in Parkinson's disease; FDA fluoxetine label). When switching from fluoxetine to selegiline, allow at least 5 weeks after the last dose of fluoxetine, because fluoxetine and norfluoxetine are cleared so slowly (selegiline SmPC, sections 4.3 and 4.5; FDA label for the selegiline patch; FDA fluoxetine label). The FDA label for selegiline in Parkinson's disease allows an even longer gap after prolonged or high-dose fluoxetine. If a patient is already taking both, stop both immediately at the first signs of serotonin syndrome and start supportive treatment (FDA label for the selegiline patch; FDA fluoxetine label). The fluoxetine SmPC allows cyproheptadine or dantrolene for such a reaction. No selegiline dose reduction is needed for fluoxetine's inhibition of CYP3A4. The FDA label for the selegiline patch requires no dose adjustment with CYP3A4 inhibitors, and in the FDA label for selegiline in Parkinson's disease itraconazole did not change selegiline pharmacokinetics.

Mechanism

Selegiline irreversibly inhibits monoamine oxidase (MAO), the enzyme that breaks down catecholamines and serotonin. At recommended doses it acts mainly on MAO type B (MAO-B) and loses this selectivity above 10 mg a day (selegiline SmPC; US Food and Drug Administration (FDA) selegiline label). In patients taking MAO inhibitors, therapeutic doses of meperidine have occasionally caused unpredictable, severe and sometimes fatal reactions, and the mechanism is unclear (FDA meperidine label). The combination can cause acute excitation or depression of the central nervous system, with high or low blood pressure (meperidine SmPC). Because MAO inhibition is irreversible, the risk persists after stopping selegiline until the body makes new enzyme. Liver enzymes play no part here: selegiline does not inhibit CYP3A4 or CYP2B6, which break down meperidine (FDA selegiline and meperidine labels).

Symptoms

The reaction takes two forms. One resembles acute opioid overdose, with coma, severe respiratory depression, cyanosis and hypotension; the other shows hyperexcitability, seizures, tachycardia, hyperpyrexia and hypertension, sometimes as serotonin syndrome with agitation, hyperthermia, diarrhoea, sweating, tremor and impaired consciousness (US Food and Drug Administration (FDA) meperidine label). Patients given selegiline with meperidine have had stupor, muscle rigidity, severe agitation, hallucinations and raised temperature, and deaths have occurred; symptoms usually resolve over days once the combination is stopped (FDA selegiline label). Serotonin syndrome usually starts within several hours to a few days of combined use but can appear later (FDA meperidine label).

Management

The combination is contraindicated (selegiline SmPC, sections 4.3 and 4.5; meperidine SmPC, sections 4.3 and 4.5; US Food and Drug Administration (FDA) selegiline and meperidine labels, section 4). Start meperidine no earlier than 14 days after the last dose of selegiline (meperidine SmPC, section 4.3; FDA selegiline and meperidine labels, section 4). Switching to another opioid does not lift the ban: selegiline is contraindicated with opioids as a class (selegiline SmPC, section 4.3), with tramadol and methadone among the examples (FDA selegiline label). General anaesthesia in a patient taking selegiline calls for caution. Monoamine oxidase inhibitors, selegiline included, can potentiate the central nervous system depressants used in anaesthesia, with reports of transient respiratory and cardiovascular depression, hypotension and coma (selegiline SmPC, section 4.4). If serotonin syndrome is suspected, stop meperidine (FDA meperidine label). Symptoms usually resolve over days once the combination is stopped (FDA selegiline label). Intravenous hydrocortisone or prednisolone have been used for severe reactions, with intravenous chlorpromazine added for hypertension and hyperpyrexia; the usefulness and safety of opioid overdose reversal agents in this reaction are unknown (FDA meperidine label).

Mechanism

Selegiline irreversibly inhibits monoamine oxidase type B (MAO-B), and enzyme activity recovers only as new enzyme is made (selegiline summary of product characteristics, SmPC, section 5.2). After a single 10 mg dose, platelet MAO-B activity returns to normal in about 2 weeks (selegiline SmPC, section 5.2). Pseudoephedrine constricts blood vessels through alpha-1 adrenergic receptors. It also enters sympathetic nerve fibres, where it displaces noradrenaline from storage vesicles (pseudoephedrine SmPC, section 5.1). Monoamine oxidase (MAO) inhibitors, selegiline included, increase catecholamine release and can prolong and intensify the vasopressor and cardiac stimulant effects of pseudoephedrine (pseudoephedrine SmPC, section 4.5). Selegiline should not be combined with sympathomimetics because of the risk of hypertension (selegiline SmPC, section 4.5). Above the recommended 10 mg, it may lose its selectivity for MAO-B, which raises the risk of hypertension (selegiline SmPC, section 4.4).

Symptoms

According to the pseudoephedrine summary of product characteristics (SmPC), combining it with monoamine oxidase (MAO) inhibitors can cause severe hypertension, hyperpyrexia and headache (section 4.5). Uncontrolled hypertension, including hypertensive crisis, has been reported when the usual dose of selegiline was combined with ephedrine, of which pseudoephedrine is a stereoisomer (selegiline labels, US Food and Drug Administration, FDA; pseudoephedrine SmPC, section 5.1). Pseudoephedrine alone at the usual dose can raise blood pressure, cause tachycardia and stimulate the central nervous system (pseudoephedrine SmPC, section 4.4). Warning signs that call for stopping pseudoephedrine are hypertension, tachycardia, palpitations, arrhythmias, nausea, and new or worsening headache (pseudoephedrine SmPC, section 4.4).

Management

The combination is contraindicated. The selegiline summary of product characteristics (SmPC) rules it out (sections 4.3 and 4.5). The pseudoephedrine SmPC names selegiline among the monoamine oxidase inhibitors, or MAOIs (sections 4.3 and 4.5). The over-the-counter pseudoephedrine label of the US Food and Drug Administration (FDA) also rules out the combination. Selegiline should not be combined with any sympathomimetic, nasal decongestants included (selegiline SmPC, sections 4.3 and 4.5). Do not take pseudoephedrine within 2 weeks after stopping selegiline (pseudoephedrine SmPC, section 4.3; FDA pseudoephedrine label). Section 4.5 of the pseudoephedrine SmPC gives 15 days. Ask the patient to report all prescription and over-the-counter medicines they take or plan to take, especially cold medicines (FDA label of selegiline orally disintegrating tablets, section 17). Patients who are not sure whether a prescription drug is an MAOI are advised to check before taking pseudoephedrine (FDA pseudoephedrine label). Stop pseudoephedrine if hypertension, tachycardia, palpitations, arrhythmias, nausea or headache appear (pseudoephedrine SmPC, section 4.4). The patient should report severe headache, unusual new symptoms or very high blood pressure to a doctor straight away (FDA label of selegiline orally disintegrating tablets, section 17). Do not raise the dose of selegiline tablets or capsules above 10 mg a day (selegiline SmPC, sections 4.2 and 4.4; FDA selegiline capsules label).

Mechanism

Selegiline irreversibly inhibits monoamine oxidase (MAO), the enzyme that breaks down catecholamines and serotonin. At recommended doses it acts mainly on MAO type B (MAO-B) and loses this selectivity above 10 mg a day (selegiline SmPC; US Food and Drug Administration (FDA) selegiline label). Sertraline is a selective serotonin reuptake inhibitor: it stops nerve endings from taking serotonin back up. Selegiline slows serotonin breakdown, so serotonin builds up and serotonin syndrome can follow (sertraline SmPC, section 4.3; FDA sertraline label). Severe reactions have occurred even at the usual selegiline dose of 10 mg a day combined with sertraline, fluoxetine or paroxetine, and their mechanism is not fully understood (FDA selegiline label). Selegiline appears among the irreversible MAO inhibitors in the sertraline summary of product characteristics. The waiting times for this group therefore apply when switching between the two drugs (sertraline SmPC, section 4.5).

Symptoms

Combining selegiline with selective serotonin reuptake inhibitors, the class sertraline belongs to, can cause confusion, hypomania, hallucinations and manic episodes, agitation, myoclonus, hyperreflexia, incoordination, shivering, tremor, seizures, ataxia, sweating, diarrhoea, fever and hypertension, all of which can be part of serotonin syndrome (selegiline SmPC, section 4.5). Patients who started sertraline soon after stopping a monoamine oxidase inhibitor, or the other way round, have had tremor, myoclonus, sweating, nausea, vomiting, flushing, dizziness, hyperthermia resembling neuroleptic malignant syndrome and seizures, and some cases were fatal (sertraline SmPC, section 4.5). Tachycardia, labile blood pressure, muscle rigidity, delirium and coma can also occur (US Food and Drug Administration (FDA) sertraline label).

Management

The combination is contraindicated (selegiline SmPC, sections 4.3 and 4.5; sertraline SmPC, sections 4.3 and 4.5, which give selegiline as an example; US Food and Drug Administration (FDA) sertraline label, section 4 and the table in section 7.1). Start sertraline no earlier than 14 days after stopping selegiline (sertraline SmPC, section 4.3; FDA sertraline and selegiline labels). When switching the other way, stop sertraline at least 7 days before the first dose of selegiline (sertraline SmPC, section 4.3). If a patient is already taking both, stop sertraline and selegiline immediately at the first signs of serotonin syndrome and start supportive symptomatic treatment (FDA sertraline label, section 5.2).

Mechanism

Selegiline at high doses loses MAO-B selectivity and inhibits MAO-A. Serotonin syndrome risk with triptans.

Symptoms

Agitation, tachycardia, hypertension.

Management

The AEMPS label for selegiline lists the combination with triptans as contraindicated because of serotonin syndrome. For a migraine attack on selegiline, use paracetamol or an NSAID.

Mechanism

Selegiline inhibits monoamine oxidase type B (MAO-B) (selegiline SmPC). The selegiline SmPC warns that above the recommended 10 mg a day it may lose its selectivity for MAO-B, and the US Food and Drug Administration (FDA) selegiline label says that selectivity may be incomplete even at the recommended dose. Tramadol is an opioid that inhibits noradrenaline reuptake and enhances serotonin release (tramadol SmPC). The FDA label for selegiline in Parkinson's disease reports serious, sometimes fatal reactions when opioids, tramadol included, were combined with MAO inhibitors, including selective MAO-B inhibitors. The FDA tramadol label specifies that this interaction presents as serotonin syndrome or opioid toxicity, and that MAO inhibitors raise the risk of seizures on tramadol.

Symptoms

Serotonin syndrome: agitation, hallucinations, confusion, fever, tachycardia, labile blood pressure, hyperreflexia, muscle rigidity, incoordination, nausea, vomiting, diarrhoea (FDA tramadol label). Seizures may occur. The interaction of MAO inhibitors with opioids can also present as opioid toxicity: respiratory depression up to coma (FDA tramadol label).

Management

The combination is contraindicated. The selegiline SmPC prohibits selegiline with opioids, and the US Food and Drug Administration (FDA) selegiline labels name tramadol directly. The Spanish and FDA tramadol labels contraindicate tramadol in patients who are taking MAO inhibitors or have taken them within the last 14 days, and selegiline is an MAO-B inhibitor (selegiline SmPC). So tramadol is started no earlier than 14 days after selegiline is stopped (tramadol labels; FDA label for selegiline in Parkinson's disease). For the reverse switch, the FDA label for transdermal selegiline requires waiting 4 to 5 half-lives of the drug and its active metabolites after the last tramadol dose, about one week. If a patient has received both drugs, watch for signs of serotonin syndrome and stop tramadol at once if it is suspected (FDA tramadol label).