Selegiline 5 mg

At high doses, selegiline is a nonselective inhibitor of MAO. Patients receiving high doses of selegiline are susceptible to hypertensive reactions induced by tyramine-rich foods and beverages (e.g., cheese, red wine, beer, pickled fish, caviar, smoked or cured meats, liver, yeast extract, or meat extracts such as Bovril, Oxo or Marmite). Do not exceed the recommended daily dose.

Administration with a high-fat meal increases the bioavailability of selegiline.

The pharmacokinetics and pharmacodynamics of selegiline are not affected by polymorphisms in the gene coding for CYP2D6, as defined by the debrisoquine metabolic ratio, or CYP2C19, as determined by the mephenytoin hydroxylator phenotype.

urinary retention.

diarrhea.

anemia.

generalized aches, leg pain, lower back pain.

weight loss.

anxiety, lethargy, malaise.

hair loss.

Cardiac arrhythmias (including tachycardia and sinus bradycardia), palpitations, hypertension, hypotension, orthostatic hypotension, syncope, peripheral edema, angina pectoris and exacerbation of angina pectoris have been reported in patients receiving selegiline.

Parkinson's disease occurs principally in patients aged >50 years, therefore it is expected that selegiline will be used primarily in geriatric patients.

Initial management of MAO inhibitor overdose should focus first on establishing the airway and stabilizing the heart rate and blood pressure, and subsequently on management of rhabdomyolysis, hyperthermia, seizures and muscle rigidity. Gut decontamination with activated charcoal can be considered within 2 hours of overdose once the patient is stabilized.

Because severe hypertension is often short-lived, it is important to use agents with a shorter duration of action such as nitroprusside, nitroglycerin or phentolamine. These drugs should be titrated to response. Beta-blockers, including labetalol, should not be used.

Hyperthermia should be aggressively managed using ice packs, evaporative cooling, cooling blankets, or extracorporeal cooling methods. Benzodiazepines are useful for muscle rigidity, seizures and agitation. Dysrhythmias can be treated with lidocaine. Once the patient is stable, a dose of activated charcoal 1 g/kg may be given if overdose occurred within the previous 2 hours. Gastric lavage can be considered within 1 hour of massive ingestions; consultation with a regional poison control centre is advised.

Consideration should be given to the possibility of mixed overdose and its potential medical implications.

The MAO-B selectivity of selegiline is lost at doses above 10 mg daily. The information presented here pertains to MAO inhibitors in general, as there is limited experience with selegiline in overdose.

Clinical effects of excessive MAO inhibition result from accumulation of amines such as serotonin and norepinephrine. Initial symptoms include hypertension, drowsiness, dizziness, confusion, tremors and headache, which may progress to agitation, muscle rigidity and seizures. Dysrhythmias, sweating, chills and hyperthermia can also occur. Late phase symptoms include hypotension, bradycardia, cardiovascular collapse, respiratory depression, pulmonary edema and coma. Potential complications include rhabdomyolysis, hemolysis, disseminated intravascular coagulation, acute renal failure (secondary to hypotension or rhabdomyolysis) and hypertensive crisis.

The risk of hypertensive crisis is increased in the presence of drugs such as amphetamines, cocaine, decongestants (e.g., pseudoephedrine, phenylephrine) or foods containing tyramine (see Drug Interactions, Drug-Food Interactions). Other overdose symptoms may be exacerbated by co-ingestion of serotonergic drugs such as dextromethorphan, ergotamine, L-tryptophan, mirtazapine, pethidine (meperidine), sibutramine, SSRIs, SNRIs (duloxetine, venlafaxine), TCAs, triptans (except eletriptan, naratriptan).

Combined use of selegiline and TCAs has been associated with a syndrome comprised of agitation, diaphoresis, changes in behaviour and in mental status, hyperpyrexia, hypertension, muscular rigidity or myoclonus, altered consciousness, restlessness, syncope, tremors, and rarely, fatalities. Similar reactions have been reported in patients receiving selegiline in combination with SSRIs (e.g., fluoxetine, paroxetine, sertraline). As it is not possible to identify patients at risk of such reactions, it seems prudent to avoid use of TCAs or SSRIs in patients receiving selegiline. If these combinations are used, patients should be counseled accordingly and monitored closely. At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with a TCA or an SSRI other than fluoxetine. Fluoxetine and its active metabolite, norfluoxetine, have very long half-lives; thus, the interval between discontinuation of fluoxetine and initiation of selegiline therapy should be five weeks.

Exacerbation of levodopa-associated dyskinesias can occur (e.g., blepharospasm, bradykinesia, dystonic manifestations, facial grimacing, festination, “freezing”, tremor, involuntary movements, loss of balance, speech problems, stiff neck, tardive dyskinesia), presumably as the result of increased dopamine availability in the CNS.

Apathy, anxiety, depression, delusions, hallucinations, insomnia, irritability, psychosis/behaviour/mood changes, overstimulation, restlessness, sleep disturbances and vivid dreams may occur, presumably as the result of increased dopamine availability in the CNS and the presence of the amphetamine metabolites of selegiline.

Hypertensive reactions, including hypertensive crisis, have been associated with selegiline and consumption of tyramine-rich foods (see Drug Interactions, Drug-Food Interactions). Patients should be counseled on the need to avoid or minimize consumption of tyramine-rich foods.

Selegiline is rapidly distributed throughout the body and has a large volume of distribution (Vd). The apparent Vd was 508 L after administration of a 10 mg iv dose. The drug is highly bound to plasma proteins. Despite the relatively short half-lives of selegiline and desmethylselegiline, the AUC of both compounds increases significantly during multiple dosing, a phenomenon that has been interpreted as an indication of saturable tissue binding.

Selegiline is rapidly absorbed after oral administration. Peak plasma concentrations ranging from 0.9 to 2.7 ng/mL were detected within 0.5 to 0.9 hours after oral administration in the fasting state. Because of extensive first-pass metabolism, the oral bioavailability of the drug is approximately 10% after administration of a 10 mg oral dose. Administration with a high-fat meal increases the bioavailability of selegiline.

Selegiline is a selective and irreversible inhibitor of monoamine oxidase type B. The principal site of action for selegiline in the treatment of Parkinson's disease is the nigrostriatal pathway in the CNS. Inhibition of MAO-B in the striatum slows breakdown of dopamine.

At doses used for the treatment of Parkinson's disease, selegiline does not inhibit peripheral metabolism of catecholamines. At doses higher than those used for the treatment of Parkinson's disease (i.e., >10 mg/day) selegiline does inhibit MAO-A.

Selegiline undergoes extensive first-pass metabolism in the gut wall and liver after absorption from the gastrointestinal tract.

The terminal elimination half-life of selegiline is 1.6 hours after administration of a 10 mg iv dose and 1.2 to 1.8 hours after administration of a single oral 10 mg dose. Total body clearance of selegiline is estimated to occur at a rate of 240 L/hour.

Three metabolites of selegiline have been identified, all of which are pharmacologically active. N-desmethylselegiline (t_½ 2.0 hours), the major metabolite of selegiline, is also an irreversible inhibitor of MAO in humans. The other metabolites are L-amphetamine (t_½ 17.7 hours) and L-methamphetamine (t_½ 20.5 hours), both of which have CNS stimulant properties.

Metabolism of selegiline is mediated mainly by CYP2B6 and CYP1A2. CYP3A4 and CYP2D6 do not appear to be involved in its metabolism. Whether CYP2C19 plays a role is not clear.