Moclobemide

Mechanism

Moclobemide inhibits monoamine oxidase (MAO), mainly type A, and slows the breakdown of noradrenaline, dopamine and serotonin (moclobemide summary of product characteristics, SmPC, section 5.1). Dextromethorphan combined with drugs that affect serotonin metabolism, MAO inhibitors included, has caused life-threatening serotonin syndrome (dextromethorphan SmPC, section 4.4). According to the dextromethorphan SmPC, severe reactions with MAO inhibitors, moclobemide among them, may also result from slower breakdown of dextromethorphan in the liver (section 4.5). Moclobemide inhibits MAO reversibly, and its half-life is about 3 hours (moclobemide SmPC, sections 5.1 and 5.2). Even so, the dextromethorphan SmPCs require a 14-day interval after stopping any MAO inhibitor, moclobemide included (sections 4.3 and 4.5).

Symptoms

When combined with dextromethorphan, monoamine oxidase (MAO) inhibitors, moclobemide included, have caused serotonin syndrome with agitation, sweating, rigidity and hypertension (dextromethorphan summary of product characteristics, SmPC, section 4.5). According to the SmPC of dextromethorphan orodispersible tablets, nausea, coma, hypotension, leg tremor, muscle spasms and hyperpyrexia can also occur, up to myocardial infarction and death (section 4.5). Serotonin syndrome may include changes in mental state, autonomic instability, neuromuscular abnormalities and gastrointestinal symptoms (dextromethorphan and moclobemide SmPCs, section 4.4). Isolated cases of serious central nervous system adverse reactions have occurred after moclobemide and dextromethorphan were taken together (moclobemide SmPC, section 4.5).

Management

The combination is contraindicated. The moclobemide summary of product characteristics (SmPC) lists dextromethorphan (section 4.3). The dextromethorphan SmPCs name moclobemide among the monoamine oxidase inhibitors, or MAOIs (sections 4.3 and 4.5). The over-the-counter dextromethorphan label of the US Food and Drug Administration (FDA) also rules out the combination. Do not take dextromethorphan within 14 days after stopping moclobemide (dextromethorphan SmPCs, sections 4.3 and 4.5; FDA dextromethorphan label). Cough and cold medicines may contain dextromethorphan. Patients taking moclobemide are told not to use them without checking first, and cough is treated with products that do not contain dextromethorphan (moclobemide SmPC, sections 4.4 and 4.5). Patients who are not sure whether a prescription drug is an MAOI are advised to check before taking dextromethorphan (FDA dextromethorphan label). If serotonin syndrome is suspected, stop dextromethorphan (dextromethorphan SmPCs, section 4.4) and, depending on the severity of symptoms, reduce the moclobemide dose or stop moclobemide as well (moclobemide SmPC, section 4.4). Benzodiazepines can be used for seizures, and benzodiazepines with external cooling for hyperthermia caused by serotonin syndrome (dextromethorphan SmPCs, section 4.9).

Mechanism

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI). Moclobemide reversibly inhibits monoamine oxidase (MAO), mainly type A, and slows the breakdown of serotonin, noradrenaline and dopamine (moclobemide summary of product characteristics, SmPC, section 5.1). Drugs that impair serotonin metabolism, that is, MAO inhibitors, increase the risk of life-threatening serotonin syndrome with SSRIs (fluvoxamine label, US Food and Drug Administration, FDA, section 5.2). Moclobemide inhibits the enzyme CYP2C19 and can raise plasma levels of fluvoxamine (moclobemide SmPC, section 4.5). Fluvoxamine in turn strongly inhibits CYP2C19, which partly breaks down moclobemide. According to the moclobemide SmPC, such changes are generally not therapeutically important and should not need a dose change (fluvoxamine and moclobemide SmPCs, section 5.2). The half-life of fluvoxamine is 13–15 hours after a single dose and 17–22 hours with repeated dosing (fluvoxamine SmPC, section 5.2).

Symptoms

Serotonin syndrome during fluvoxamine treatment can be life-threatening, especially with other serotonergic drugs. It brings hyperthermia, rigidity, myoclonus and autonomic instability with rapid swings in vital signs. Mental changes include confusion, irritability and extreme agitation progressing to delirium and coma (fluvoxamine summary of product characteristics, SmPC, section 4.4). When moclobemide has been combined with antidepressants, fluvoxamine among them, isolated cases of hyperthermia, confusion, hyperreflexia and myoclonus have occurred (moclobemide SmPC, section 4.5). Hallucinations, tachycardia, dizziness, sweating, flushing, tremor, incoordination, seizures, nausea, vomiting and diarrhoea are also possible (fluvoxamine label, US Food and Drug Administration, FDA, section 5.2).

Management

The combination is contraindicated (fluvoxamine summary of product characteristics, SmPC, sections 4.3 and 4.5; fluvoxamine label, US Food and Drug Administration, FDA, section 4). The moclobemide SmPC is softer: it lists fluvoxamine among antidepressants to give with caution alongside moclobemide (moclobemide SmPC, section 4.5). The strictest document applies. The documents differ on switching intervals. The Spanish fluvoxamine SmPC names moclobemide as a reversible monoamine oxidase inhibitor (MAOI) and allows fluvoxamine to start the day after moclobemide is stopped (fluvoxamine SmPC, section 4.3). The moclobemide SmPC says the same for any antidepressant (section 4.5). The FDA label requires at least 14 days after stopping an MAOI used for psychiatric disorders (FDA fluvoxamine label, sections 2.4 and 4). When switching the other way, allow at least one week between the last dose of fluvoxamine and the first dose of an MAOI (fluvoxamine SmPC, section 4.3) or at least 14 days (FDA fluvoxamine label, sections 2.4 and 4). The moclobemide SmPC asks prescribers to consider the half-life of the previous selective serotonin reuptake inhibitor (moclobemide SmPC, section 4.5). Do not stop fluvoxamine abruptly. Taper the dose over at least one to two weeks (fluvoxamine SmPC, section 4.2). If signs of serotonin syndrome appear, stop fluvoxamine and other serotonergic drugs at once and start symptomatic treatment (fluvoxamine SmPC, section 4.4; FDA fluvoxamine label, section 5.2). Keep the patient under medical supervision and admit to hospital if needed (moclobemide SmPC, section 4.5).

Mechanism

Moclobemide reversibly inhibits monoamine oxidase (MAO), mainly subtype A, and slows the breakdown of serotonin, noradrenaline and dopamine (moclobemide SmPC). Tramadol is an opioid that inhibits noradrenaline reuptake and enhances serotonin release (tramadol SmPC). Together they can cause life-threatening serotonin syndrome. The tramadol SmPC warns of a second risk: patients who received MAO inhibitors before the opioid pethidine had life-threatening reactions affecting the nervous system, breathing and circulation, and the same reactions cannot be ruled out with tramadol. The US Food and Drug Administration (FDA) tramadol label adds that MAO inhibitors raise the risk of seizures on tramadol.

Symptoms

Serotonin syndrome: agitation, hallucinations, confusion, fever, tachycardia, labile blood pressure, hyperreflexia, myoclonus, muscle rigidity, incoordination, nausea, vomiting, diarrhoea (moclobemide and tramadol labels). 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 moclobemide SmPC prohibits it with tramadol by name. The tramadol SmPC contraindicates tramadol in patients who are taking MAO inhibitors or have taken them within the last 14 days, and the US Food and Drug Administration (FDA) tramadol label sets the same 14-day ban. So tramadol is started no earlier than 14 days after the last moclobemide dose (tramadol labels). The FDA tramadol label also says not to start an MAO inhibitor while taking tramadol. 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). Withdrawal of the serotonergic drugs usually brings rapid improvement (tramadol SmPC).

Mechanism

Moclobemide is a reversible inhibitor of monoamine oxidase A (MAO-A), the enzyme that breaks down serotonin and clears zolmitriptan and its active N-desmethyl metabolite. After moclobemide, zolmitriptan exposure (AUC) rose by 26% and the AUC of the active metabolite rose 3-fold (zolmitriptan SmPC, AEMPS, section 4.5). Zolmitriptan is a 5-HT1B/1D agonist and moclobemide raises serotonin levels, so their serotonergic effects add up. The moclobemide SmPC lists triptans among contraindicated combinations, and the FDA label of zolmitriptan contraindicates use with any MAO-A inhibitor.

Symptoms

The main danger is serotonin syndrome: spontaneous or inducible clonus, agitation and sweating, tremor and hyperreflexia, hypertonia with a temperature above 38 °C, confusion, swings in heart rate and blood pressure, nausea, vomiting, diarrhoea (zolmitriptan SmPC, AEMPS, and FDA label). Symptoms usually start within minutes to hours after a new or higher dose of a serotonergic drug (FDA label of zolmitriptan). Higher zolmitriptan exposure also strengthens its own effects: heaviness, pressure or tightness in the chest, throat and neck, and a rise in blood pressure.

Management

The combination is contraindicated: the moclobemide SmPC lists triptans among contraindicated drugs and names zolmitriptan explicitly (moclobemide SmPC, AEMPS, sections 4.3 and 4.5). The FDA label of zolmitriptan contraindicates it in patients taking an MAO-A inhibitor or within 2 weeks of stopping one (FDA label of zolmitriptan, sections 4 and 7.2). The Spanish zolmitriptan SmPC is softer: with an MAO-A inhibitor it caps the dose at 5 mg per 24 hours and bans the combination only when moclobemide exceeds 150 mg twice daily (zolmitriptan SmPC, AEMPS, sections 4.2 and 4.5). The strictest document wins, so do not prescribe zolmitriptan to a patient on moclobemide. After stopping moclobemide, allow zolmitriptan no earlier than 2 weeks later (FDA label of zolmitriptan, section 4). If the patient has taken the drugs together and signs of serotonin syndrome appear, stop both serotonergic drugs. Withdrawal brings rapid improvement, and further treatment depends on the severity of symptoms (zolmitriptan SmPC, AEMPS, section 4.4; FDA label of zolmitriptan, section 5.7).