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MAO-B INHIBITORS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) These agents are irreversible monoamine oxidase inhibitors which serve as selective inhibitors of type B. At high doses this selectivity may be lost, and manifestations of non-selective MAOI intoxication may develop.
    B) Selegiline at low doses is an irreversible type B MAOI. Two of its metabolites, L-methamphetamine and L-amphetamine, may be responsible for some of the side effects reported with therapy.
    C) Rasagiline (N-propargyl-1R(+)-aminoindan; TVP-1012) is a selective and irreversible inhibitor of monoamine oxidase type B (MAO-B), with structural similarity to selegiline.

Specific Substances

    A) SELEGILINE
    1) Selegiline hydrochloride
    2) CAS 14611-51-9 (selegiline)
    3) CAS 2079-54-1 (selegiline hydrochloride)
    4) CAS 14611-52-0 (selegiline hydrochloride)
    RASAGILINE MESILATE
    1) Rasagiline Mesylate
    2) Rasagilini Mesilas
    3) CAS 136236-51-6 (rasagiline)
    4) CAS 161735-79-1 (rasagiline mesilate)
    LAZABEMIDE
    1) Lazabemida
    2) Lazabemidum
    3) CAS 103878-84-8 (lazabemide)
    4) CAS 103878-83-7 (lazabemide hydrochloride)
    PARGYLINE HYDROCHLORIDE
    1) Pargyline
    2) CAS 555-57-7 (pargyline)
    3) CAS 306-07-0 (pargyline hydrochloride)

Available Forms Sources

    A) FORMS
    1) SELEGILINE is available in 5 mg tablets and capsules, and as an orally disintegrating tablet containing 1.25 mg of selegiline hydrochloride (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006; Prod Info selegiline hcl oral tablets, 2003). It is also available in a transdermal system and supplied as 6 mg/24 hours (20 mg/20 cm(2)), 9 mg/24 hours (30 mg/30 cm(2)), or 12 mg/24 hours (40 mg/40 cm(2) patches for daily use in boxes of 30 (Prod Info EMSAM(R) transdermal patch, 2008).
    2) RASAGILINE is available in 0.5 mg and 1 mg tablets and supplied in bottles of 30 (Prod Info AZILECT(R) oral tablets, 2006)
    B) USES
    1) SELEGILINE is intended for use with levodopa/carbidopa therapy in patients with Parkinson's disease (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006). It has also been used in the treatment of major depressive disorder (Prod Info EMSAM(R) transdermal patch, 2006).
    2) RASAGILINE MESYLATE is also used for the treatment of idiopathic Parkinson's disease as either an initial monotherapy and as an adjunct to levodopa (Prod Info AZILECT(R) oral tablets, 2006).
    3) Pargyline is a MAOI that was formerly used in the treatment of moderate to severe hypertension. Lazabemide was being investigated for use in the treatment of Parkinson's but development was discontinued due to the risk of severe hepatotoxicity (Sweetman, 2007).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Selective monoamine oxidase type B inhibitors (MAO-BIs) are primarily used for the treatment of Parkinson disease. A transdermal formulation of selegiline is used for depression. The 2 MAO-BIs approved for use in the United States are selegiline and rasagiline. For information on nonselective MAOIs (eg, isocarboxazid, phenelzine, and tranylcypromine), refer to "Monoamine oxidase inhibitors (MAO)" management. For information on selective inhibitors of MAO-A (eg, moclobemide), please refer to "Reversible MAO-A Inhibitors" management.
    B) PHARMACOLOGY: MAO-B is present in the brain in dopaminergic raphe neurons, platelets, and pancreas. MAO-BIs inhibit the function of MAO-B, preventing the degradation of monoamine neurotransmitters (dopamine, norepinephrine). Selegiline and rasagiline are irreversible inhibitors of the enzyme.
    C) TOXICOLOGY: In general, MAO-B selective inhibitors are much less toxic than nonspecific MAO inhibitors. There are no reported deaths from selegiline or rasagiline overdose. Theoretically, at high doses, MAO type selectivity may be lost and MAO-A may be inhibited as well. This could lead to excessive catecholamines and a hyperadrenergic state. Toxicity may occur after an overdose or when MAOIs are combined with other drugs with MAO or serotonergic activity.
    D) EPIDEMIOLOGY: Overdose of MAO-BIs is uncommon and severe effects or deaths are extremely rare.
    E) WITH THERAPEUTIC USE
    1) Orthostatic hypotension, anorexia, nausea, dyspepsia, dyskinesia, hallucinations, and headache are reported. Selegiline is converted to L-methamphetamine and may cause hypertension and tachycardia following therapeutic dosing. Because most MAOIs are irreversible, symptoms may persist for weeks after discontinuation of therapy. Rasagiline, a secondary cyclic benzylamine propargylamine derivative, has no amphetamine metabolites and therefore, sympathomimetic adverse events are not anticipated. Dyskinesia has been reported with rasagiline therapy.
    2) DRUG INTERACTION: Pseudoephedrine and phenylephrine may augment catecholamine release and cause or exacerbate toxicity when taken with MAOIs. Serotonin syndrome may be precipitated by coadministration with other serotonergic agents such as illicit drugs (eg, ecstacy/MDMA), medications (eg, dextromethorphan, SSRIs, meperidine), and herbal supplements (eg, St John's Wort). There is no evidence that tyramine reactions occur in patients taking MAO-BI.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: There are no quality reports of significant toxicity following MAO-B selective inhibitors overdose. However, there is a theoretical risk of tachycardia, mild hypertension, anxiety, flushing, and headache in patients with mild to moderate toxicity.
    2) SEVERE POISONING: There are no quality reports of significant toxicity following MAO-B selective inhibitors overdose. However, it is possible that a large overdose could present with symptoms similar to a nonselective MAOI overdose. Based on what is known about nonselective MAOI overdose, these effects might include hyperadrenergic symptoms, such as severe tachycardia and hypertension, diaphoresis, delirium, seizures, dysrhythmias, and possibly cardiovascular collapse and coma, may occur.
    3) Serotonin syndrome is another theoretical complication from MAO-BI toxicity. It presents with a triad of autonomic instability (ie, hyperthermia, hypertension, hypotension), neuromuscular excitability (ie, clonus and rigidity), and altered mental status that may be thought of as a spectrum of symptoms. Multiorgan failure and death may result from any of these complications.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) RASAGILINE: Hyperthermia was reported with rasagiline administration in clinical trials. The incidence of hyperthermia was 3% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily compared with 1% (n=151) of patients taking placebo (Prod Info AZILECT(R) oral tablets, 2006).
    0.2.20) REPRODUCTIVE
    A) Selegiline and rasagiline are classified as FDA pregnancy category C. No clear association between monoamine oxidase inhibitors and teratogenic effects in humans has been found; however, there is the possibility of hypertensive crisis which could severely impact the fetus. In animal studies of selegiline and rasagiline, there was evidence of teratogenicity, increased postimplantation loss, and decreased fetal weights. During lactation in rats, concentrations of selegiline and its metabolites were approximately 15 and 5 times, respectively, that found in plasma which indicated direct dosing of pups during lactation. Prolactin secretion was inhibited by rasagiline in rat studies. Slight decreases in sperm concentration and total sperm count were reported at the highest dose when male rats were given transdermal doses of selegiline.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) MAO-BI plasma concentrations are not clinically useful or readily available.
    C) Screening urine toxicology immunoassays will not detect MAOIs. Selegiline is converted to amphetamine which may be detected on a urine toxicology screen.
    D) In symptomatic patients, obtain a basic chemistry profile, lactate, CPK, ECG, renal function, and coagulation panel. Obtain cardiac enzymes in a patient with chest pain.
    E) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection in a patient with an altered mental status.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) All patients with symptoms of MAOI toxicity should be evaluated by a health care professional. Symptoms may persist for several weeks due to the irreversibility of MAO inhibition caused by these medications. Discontinuation of the offending agents and patient education involving drug interactions should be provided to all symptomatic patients.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Careful attention to the ABCs (airway, breathing and circulation) should guide symptomatic and supportive treatment, which is the mainstay of MAOI toxicity management. Orotracheal intubation for airway protection should be performed early in cases of coma or severe toxicity, especially for patients that are agitated with hyperthermia. Recognition and treatment of hyperthermia, hypertension, seizures, end-organ damage, and muscular rigidity is paramount. There is no antidote for MAOI toxicity.
    C) DECONTAMINATION
    1) PREHOSPITAL: As MAO-BI overdoses are generally not serious, there is no role for prehospital decontamination following oral exposure. Search for and remove any transdermal patches from the patient's body. Patches are often under clothing and can be found on the back, chest or upper arm.
    2) HOSPITAL: Consider decontamination if a patient presents shortly (eg, within 1 to 2 hours) after a large oral ingestion and is not manifesting symptoms of toxicity. Activated charcoal is generally not recommended in patients that are manifesting signs of toxicity as they may become comatose or seize and lose their airway. If the airway is protected with orotracheal intubation, charcoal may be given. However, it is still possible that a patient may aspirate around the endotracheal tube. Whole bowel irrigation should be considered if there is a clear ingestion of a transdermal preparation. Gastric lavage is not indicated as serious toxicity is rare.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication (coma, respiratory depression, severe agitation).
    E) ANTIDOTE
    1) None.
    F) DELIRIUM
    1) Liberal use of benzodiazepines is recommended until the patient is no longer agitated.
    G) HYPERTENSION
    1) If the patient is agitated, hypertension may respond to sedation with benzodiazepines. For severe hypertension, an alpha adrenergic receptor antagonist, such as phentolamine, or a mixed alpha and beta antagonists, such as labetalol, may be used. Rapid-acting, easily titrated vasodilators such as nitroglycerin and nitroprusside are also good choices.
    H) TACHYCARDIA
    1) Tachycardia may occur from a combination of agitation and catecholamine release. Treat with benzodiazepines. Pure beta blockade should generally be avoided in these patients, as it may exacerbate hypertension due to unopposed alpha activity.
    I) SEROTONIN SYNDROME
    1) Treat the patient aggressively with benzodiazepines and cooling, if needed. Cyproheptadine may be considered (seek guidance from a toxicologist prior to administering).
    J) HYPERTHERMIA
    1) Hyperthermia can result form psychomotor agitation, increased neuromuscular activity or persistent seizures. Sedate the patient with benzodiazepines and place in a quiet, dark environment. Other cooling measures can include cool mist and fans or packing the body in ice; consider ice water immersion for severe hyperthermia. Neuromuscular paralysis of the patient may be necessary for severe hyperthermia.
    K) DYSRHYTHMIAS
    1) Follow ACLS protocols.
    L) SEIZURES
    1) Seizures may be a result of excessive catecholamine release. Treatment includes intravenous benzodiazepines; add propofol or barbiturates if seizures recur. If seizures persist, intubate and paralyze the patient. Continuous EEG monitoring is indicated. Consider a CT scan of the head to rule out intracranial hemorrhage.
    M) HYPOTENSION
    1) Mild orthostatic hypotension is common with therapeutic use. Severe hypotension is rare, but may occur as a late and ominous finding, as a result of cardiac collapse. Hypotension should be treated with an initial bolus of NS, if a patient can tolerate a fluid load, followed by adrenergic vasopressors to raise mean arterial pressure, as needed. Direct agents (norepinephrine) are preferred to indirect agents (dopamine) because indirect pressors rely on catecholamine release from sympathetic neurons.
    N) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are not of value.
    O) PATIENT DISPOSITION
    1) HOME CRITERIA: Children should be evaluated in the hospital and observed. Adults should be evaluated by a health care professional if they have received a higher than therapeutic dose, or if they are symptomatic.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions or children with inadvertent ingestions should be sent to a health care facility for observation for 6 to 8 hours.
    3) ADMISSION CRITERIA: Patients with significant persistent hypertension, tachycardia or central nervous depression should be admitted to the hospital. Patients with coma, seizures, dysrhythmias, hyperthermia, or delirium should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    P) PITFALLS
    1) Failure to recognize or misdiagnose MAOI toxicity. Note that effects extend for many weeks and failure to wait for a "washout period" after discontinuing an MAOI and starting another medication that may interact with an MAOI can result in toxicity. Other causes of altered mental status, such as hypoxia or hypoglycemia, must be ruled out. Significant toxicity has not been reported from overdose of selegiline or rasagiline alone. Consider another etiology, if a patient has severe toxicity.
    Q) PHARMACOKINETICS
    1) Selegiline and rasagiline have good oral bioavailability. Selegiline is well absorbed transdermally. Both agents have large volumes of distribution and extensive hepatic metabolism.
    R) DIFFERENTIAL DIAGNOSIS
    1) CNS infection, intracranial hemorrhage, manic or psychotic episode due to psychiatric illness, sympathomimetic intoxication (eg, cocaine, methamphetamine), ethanol/benzodiazepine/barbiturate, antipsychotic or clonidine withdrawal, hypoglycemia, hypoxia, or serotonin syndrome from another agent.

Range Of Toxicity

    A) TOXICITY: The toxic dose varies widely, depending on the specific agent. Most of MAOIs have narrow therapeutic windows. A selegiline dose of 600 mg caused hypotension and psychomotor agitation. Rasagiline 2 mg/day caused mild symptoms in healthy adults. Patients on chronic levodopa therapy developed hypertension and orthostatic hypotension with 10 g rasagiline.

Clinical Effects

Summary Of Exposure

    A) USES: Selective monoamine oxidase type B inhibitors (MAO-BIs) are primarily used for the treatment of Parkinson disease. A transdermal formulation of selegiline is used for depression. The 2 MAO-BIs approved for use in the United States are selegiline and rasagiline. For information on nonselective MAOIs (eg, isocarboxazid, phenelzine, and tranylcypromine), refer to "Monoamine oxidase inhibitors (MAO)" management. For information on selective inhibitors of MAO-A (eg, moclobemide), please refer to "Reversible MAO-A Inhibitors" management.
    B) PHARMACOLOGY: MAO-B is present in the brain in dopaminergic raphe neurons, platelets, and pancreas. MAO-BIs inhibit the function of MAO-B, preventing the degradation of monoamine neurotransmitters (dopamine, norepinephrine). Selegiline and rasagiline are irreversible inhibitors of the enzyme.
    C) TOXICOLOGY: In general, MAO-B selective inhibitors are much less toxic than nonspecific MAO inhibitors. There are no reported deaths from selegiline or rasagiline overdose. Theoretically, at high doses, MAO type selectivity may be lost and MAO-A may be inhibited as well. This could lead to excessive catecholamines and a hyperadrenergic state. Toxicity may occur after an overdose or when MAOIs are combined with other drugs with MAO or serotonergic activity.
    D) EPIDEMIOLOGY: Overdose of MAO-BIs is uncommon and severe effects or deaths are extremely rare.
    E) WITH THERAPEUTIC USE
    1) Orthostatic hypotension, anorexia, nausea, dyspepsia, dyskinesia, hallucinations, and headache are reported. Selegiline is converted to L-methamphetamine and may cause hypertension and tachycardia following therapeutic dosing. Because most MAOIs are irreversible, symptoms may persist for weeks after discontinuation of therapy. Rasagiline, a secondary cyclic benzylamine propargylamine derivative, has no amphetamine metabolites and therefore, sympathomimetic adverse events are not anticipated. Dyskinesia has been reported with rasagiline therapy.
    2) DRUG INTERACTION: Pseudoephedrine and phenylephrine may augment catecholamine release and cause or exacerbate toxicity when taken with MAOIs. Serotonin syndrome may be precipitated by coadministration with other serotonergic agents such as illicit drugs (eg, ecstacy/MDMA), medications (eg, dextromethorphan, SSRIs, meperidine), and herbal supplements (eg, St John's Wort). There is no evidence that tyramine reactions occur in patients taking MAO-BI.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: There are no quality reports of significant toxicity following MAO-B selective inhibitors overdose. However, there is a theoretical risk of tachycardia, mild hypertension, anxiety, flushing, and headache in patients with mild to moderate toxicity.
    2) SEVERE POISONING: There are no quality reports of significant toxicity following MAO-B selective inhibitors overdose. However, it is possible that a large overdose could present with symptoms similar to a nonselective MAOI overdose. Based on what is known about nonselective MAOI overdose, these effects might include hyperadrenergic symptoms, such as severe tachycardia and hypertension, diaphoresis, delirium, seizures, dysrhythmias, and possibly cardiovascular collapse and coma, may occur.
    3) Serotonin syndrome is another theoretical complication from MAO-BI toxicity. It presents with a triad of autonomic instability (ie, hyperthermia, hypertension, hypotension), neuromuscular excitability (ie, clonus and rigidity), and altered mental status that may be thought of as a spectrum of symptoms. Multiorgan failure and death may result from any of these complications.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) RASAGILINE: Hyperthermia was reported with rasagiline administration in clinical trials. The incidence of hyperthermia was 3% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily compared with 1% (n=151) of patients taking placebo (Prod Info AZILECT(R) oral tablets, 2006).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) SELEGILINE: Blurred vision and diplopia have been infrequently reported during selegiline therapy (Prod Info selegiline hcl oral tablets, 2003).
    2) RASAGILINE: Conjunctivitis was reported with rasagiline administration in clinical trials. The incidence of conjunctivitis was 3% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily compared with 1% (n=151) of patients taking placebo (Prod Info AZILECT(R) oral tablets, 2006).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ORTHOSTATIC HYPOTENSION
    1) WITH THERAPEUTIC USE
    a) SELEGILINE
    1) Orthostatic hypotension has been reported as an infrequent side effect during selegiline therapy (Birkmayer, 1978). Termination of selegiline therapy or a reduction in dose corrected the hypotension.
    2) Hypotension was abolished 7 days after discontinuation of selegiline (Churchyard et al, 1997). Decreasing the dose of selegiline to 5 mg reduced the fall in systolic blood pressure but did not totally abolish the orthostatic hypotension.
    3) In 2 separate studies, selegiline was found to cause orthostatic hypotension during a head tilt test (Churchyard et al, 1997; Turkka et al, 1997). Both compared results to patients receiving placebo or levodopa alone and found decreases in systolic blood pressure (both studies), and decreases in diastolic blood pressure (Turkka study only) more pronounced in the selegiline groups. Discontinuation of selegiline reversed the abnormal response to head tilt. Selegiline appeared to diminish autonomic responses in these patients.
    b) RASAGILINE
    1) As an adjunct treatment to levodopa therapy, the incidence of orthostatic hypotension was 9% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily and 6% (n=164) for patients treated with 0.5 mg orally once daily compared with 3% (n=159) of placebo-treated patients (Prod Info AZILECT(R) oral tablets, 2006).
    B) FINDING OF INCREASED BLOOD PRESSURE
    1) WITH THERAPEUTIC USE
    a) RASAGILINE
    1) Small but significant increases in supine systolic blood pressure have been reported relative to placebo (ie, 4 mm Hg with rasagiline 2-mg doses) (Anon, 2002). This is unlikely to be clinically relevant, although effects over long-term therapy require investigation, including patients with preexisting cardiovascular disease.
    2) WITH POISONING/EXPOSURE
    a) SELEGILINE
    1) COMBINATION OVERDOSE: CASE REPORT: A 50-year-old man with a medical history of bipolar II disorder, developed coma, generalized seizures, visual hallucinations, and hypertension as high as 170/110 mmHg after ingesting 195 mg of selegiline, 8600 mg of carbamazepine, 16,000 mg of sodium valproate (sustained-release preparation), 2250 mg of trazodone, and 70 mg of nitrazepam. Following supportive care, he gradually recovered (Kobayashi et al, 2011).
    C) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Isolated instances of chest pain have been reported (Anon, 2002). Causality is uncertain.
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) QTc PROLONGATION
    a) An animal study reported prolonged QTc intervals in rabbits receiving oral selegiline (Uzun et al, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) SELEGILINE: After selegiline administration, shortness of breath has developed (Prod Info selegiline hcl oral tablets, 2003).
    b) RASAGILINE: As an adjunct treatment to levodopa therapy, the incidence of dyspnea was 3% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily and 5% (n=164) for patients treated with 0.5 mg orally once daily compared with 2% (n=159) of placebo-treated patients (Prod Info AZILECT(R) oral tablets, 2006).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has occurred during therapeutic use of these agents (Siddiqui & Plosker, 2005). It was frequently reported with rasagiline therapy (Guay, 2006).
    b) SELEGILINE: In clinical trials, headache occurred in 7% of patients treated with selegiline orally disintegrating tablets (Zelapar(TM)) compared to 6% with placebo (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006).
    c) RASAGILINE: Headache was reported with rasagiline administration in clinical trials. The incidence of headache was 14% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily compared with 12% (n=151) of patients taking placebo. As an adjunct treatment to levodopa therapy, the incidence of headache was 11% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily and 8% (n=164) for patients treated with 0.5 mg orally once daily compared with 10% (n=159) of placebo-treated patients (Prod Info AZILECT(R) oral tablets, 2006).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported with selegiline therapy (Fernandez & Chen, 2007).
    b) In clinical trials, dizziness occurred in 11% of patients treated with selegiline orally disintegrating tablets (Zelapar(TM)) compared to 8% with placebo (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006).
    C) NEUROLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials, the most common cognitive or behavioral adverse events were sleep disorders, somnolence and depression. More frequent dopaminergic effects (ie, abnormal dreams, vomiting, sleep disorders, somnolence, and ataxia) were observed in patients receiving 2 mg/day as compared to 1 mg/day (Oldfield et al, 2007).
    D) ATAXIA
    1) WITH THERAPEUTIC USE
    a) RASAGILINE
    1) As an adjunct treatment to levodopa therapy, the incidence of ataxia was 3% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily and 6% (n=164) for patients treated with 0.5 mg orally once daily compared with 1% (n=159) of placebo-treated patients (Prod Info AZILECT(R) oral tablets, 2006).
    E) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) RASAGILINE
    1) As an adjunct treatment to levodopa therapy, the incidence of dystonia was 3% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily and 2% (n=164) for patients treated with 0.5 mg orally once daily compared with 1% (n=159) of placebo-treated patients (Prod Info AZILECT(R) oral tablets, 2006).
    b) SELEGILINE
    1) CASE REPORT: A 25-year-old man with triosephosphate isomerase deficiency developed hyperkinetic torsion dystonia in the neck shoulder girdle leading to highly accentuated asymmetric hypertrophy of the neck muscles as well as psychiatric symptoms after 9 years of selegiline therapy. Symptoms began to resolve within 3 months of drug discontinuation and were absent within 6 months. Rechallenge was not attempted (Hollan et al, 2004).
    F) COMA
    1) WITH POISONING/EXPOSURE
    a) SELEGILINE
    1) COMBINATION OVERDOSE: CASE REPORT: A 50-year-old man with a medical history of bipolar II disorder, presented in coma after ingesting 195 mg of selegiline, 8600 mg of carbamazepine, 16,000 mg of sodium valproate (sustained-release preparation), 2250 mg of trazodone, and 70 mg of nitrazepam. He was treated with supportive care and was extubated on day 5, but he developed a confusional state with myoclonus and marked perspiration. He was intubated again for deterioration of the pneumonia. On day 10, his condition improved and he was extubated and transferred to a psychiatric ward. The next day, he developed generalized seizures (mostly tonic, and sometimes tonic and clonic) and frequent visual hallucinations. Despite supportive care, he continued to have seizures for the next few days. He also developed hypertension (as high as 170/110 mmHg). Following further supportive care, including treatment with IV diphenylhydantoin and oral sodium valproate, his seizures and hallucinations gradually resolved. On day 21, serum catecholamine concentrations were still high (epinephrine 157 pg/mL, norepinephrine 1264 pg/mL, and dopamine 21 pg/mL) (Kobayashi et al, 2011).
    G) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) SELEGILINE
    1) COMBINATION OVERDOSE: CASE REPORT: A 50-year-old man with a medical history of bipolar II disorder, presented in coma after ingesting 195 mg of selegiline, 8600 mg of carbamazepine, 16,000 mg of sodium valproate (sustained-release preparation), 2250 mg of trazodone, and 70 mg of nitrazepam. He was treated with supportive care and was extubated on day 5, but he developed a confusional state with myoclonus and marked perspiration. He was intubated again for deterioration of the pneumonia. On day 10, his condition improved and he was extubated and transferred to a psychiatric ward. The next day, he developed generalized seizures (mostly tonic, and sometimes tonic and clonic) and frequent visual hallucinations. Despite supportive care, he continued to have seizures for the next few days. He also developed hypertension (as high as 170/110 mmHg). Following further supportive care, including treatment with IV diphenylhydantoin and oral sodium valproate, his seizures and hallucinations gradually resolved. On day 21, serum catecholamine concentrations were still high (epinephrine 157 pg/mL, norepinephrine 1264 pg/mL, and dopamine 21 pg/mL) (Kobayashi et al, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) SELEGILINE: In clinical trials, nausea occurred in 10% to 11% of patients treated with oral selegiline hydrochloride compared to 3% to 9% with placebo, and in some cases has led to drug discontinuation (Prod Info selegiline hcl oral tablets, 2003; Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006).
    b) RASAGILINE: As an adjunct treatment to levodopa therapy, the incidence of nausea was 12% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily and 10% (n=164) for patients treated with 0.5 mg orally once daily compared with 8% (n=159) of placebo-treated patients (Prod Info AZILECT(R) oral tablets, 2006).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) RASAGILINE: As an adjunct treatment to levodopa therapy, the incidence of vomiting was 7% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily and 4% (n=164) for patients treated with 0.5 mg orally once daily compared with 1% (n=159) of placebo-treated patients (Prod Info AZILECT(R) oral tablets, 2006).
    C) ORAL IRRITATION
    1) WITH THERAPEUTIC USE
    a) SELEGILINE: In clinical trials, 10% of patients treated with selegiline orally disintegrating tablets (Zelapar(TM)) experienced oropharyngeal adverse effects (eg, mouth pain, swallowing pain, areas of focal reddening, edema, and/or ulceration) compared to 3% of patients receiving placebo (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) RASAGILINE: As an adjunct treatment to levodopa therapy, the incidence of constipation was 9% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily and 4% (n=164) for patients treated with 0.5 mg orally once daily compared with 5% (n=159) of placebo-treated patients (Prod Info AZILECT(R) oral tablets, 2006).
    E) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia was reported relatively frequently with rasagiline use. Other gastrointestinal symptoms included: gastroenteritis, abdominal pain, and gingivitis (Guay, 2006).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) GENITOURINARY SYMPTOMS
    1) WITH THERAPEUTIC USE
    a) Selegiline may infrequently cause slow urination, nocturia, prostate hypertrophy, urinary hesitancy, urinary retention, and urinary frequency (Prod Info selegiline hcl oral tablets, 2003).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISORDER OF SKIN
    1) WITH THERAPEUTIC USE
    a) SELEGILINE: Photosensitivity, hair loss, sweating, diaphoresis, facial hair, and rash have been reported infrequently with selegiline therapy (Prod Info selegiline hcl oral tablets, 2003).
    B) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) RASAGILINE: As an adjunct treatment to levodopa therapy, the incidence of sweating was 3% (n=149) for patients treated with rasagiline 1 milligram (mg) orally once daily and 2% (n=164) for patients treated with 0.5 mg orally once daily compared with 1% (n=159) of placebo-treated patients (Prod Info AZILECT(R) oral tablets, 2006).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In clinical trials, back pain occurred in 5% of patients treated with selegiline orally disintegrating tablets (Zelapar(TM)) compared to 3% with placebo (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia has been reported following initial monotherapy with rasagiline. Arthritis and neck pain have also been observed with treatment (Guay, 2006).

Reproductive

    3.20.1) SUMMARY
    A) Selegiline and rasagiline are classified as FDA pregnancy category C. No clear association between monoamine oxidase inhibitors and teratogenic effects in humans has been found; however, there is the possibility of hypertensive crisis which could severely impact the fetus. In animal studies of selegiline and rasagiline, there was evidence of teratogenicity, increased postimplantation loss, and decreased fetal weights. During lactation in rats, concentrations of selegiline and its metabolites were approximately 15 and 5 times, respectively, that found in plasma which indicated direct dosing of pups during lactation. Prolactin secretion was inhibited by rasagiline in rat studies. Slight decreases in sperm concentration and total sperm count were reported at the highest dose when male rats were given transdermal doses of selegiline.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of selegiline or rasagiline in humans (Prod Info ZELAPAR(R) oral disintegrating tablets, 2014; Prod Info EMSAM(R) transdermal system, 2014; Prod Info ELDEPRYL(R) oral capsules, 2012; Prod Info selegiline HCl oral tablets, 2009; Prod Info AZILECT(R) oral tablets, 2006).
    B) ANIMAL STUDIES
    1) SELEGILINE ORAL
    a) RABBITS: No teratogenic effects were observed at oral doses of 5, 25, and 50 mg/kg. However, due to smaller litter sizes at the two higher doses, teratogenic potential could not be evaluated (Prod Info ELDEPRYL(R) oral capsules, 2012).
    b) RATS: No teratogenic effects were observed at oral doses of 4, 12, and 36 mg/kg in a study of Sprague–Dawley rats (Prod Info ELDEPRYL(R) oral capsules, 2012).
    2) SELEGILINE TRANSDERMAL
    a) RATS: Slight increases in malformations were reported at the highest dose when pregnant rats were given transdermal selegiline 10, 30, and 75 mg/kg/day (8, 24, and 60 times the maximum recommended human dose (MRHD) of 12 mg/24 hours on a mg/m(2) basis) during the period of organogenesis. Concentrations of selegiline and its metabolites were similar in fetal and maternal plasma. In another study in which rats were given doses transdermally at 10, 30, and 75 mg/kg/day on days 6 through 21 of gestation, decreased pup weight throughout lactation and postweaning, as well as pup epididymal and testicular hypoplasia were reported at the 30 and 75 mg/kg doses (Prod Info EMSAM(R) transdermal system, 2014).
    b) RABBITS: Studies of rabbits given transdermal selegiline at doses of 2.5, 10, and 40 mg/kg/day (4, 16, and 64 times the maximum recommended human dose (MRHD) on a mg/m(2) basis) during organogenesis showed a slight increase in visceral malformations following the highest dose (Prod Info EMSAM(R) transdermal system, 2014)
    3) RASAGILINE
    a) RATS: In one study, pregnant rats were dosed with rasagiline alone at 0.1, 0.3, and 1 mg/kg/day or rasagiline combined with levodopa/carbidopa at 80/20 mg/kg/day throughout the period of organogenesis. An increased incidence of wavy ribs was reported in fetuses from the rats given combined rasagiline and levodopa/carbidopa (approximately 8 times the plasma AUC expected in humans at the maximum recommended human dose (MRHD) and 1/1 times the MRHD of levodopa/carbidopa (800/200 mg/day) on a mg/m(2) basis) (Prod Info AZILECT(R) oral tablets, 2009).
    b) RABBITS: Increased cardiovascular abnormalities were reported at all doses of rasagiline (1 to 13 times the plasma rasagiline AUC at the MRHD) when pregnant rabbits were given rasagiline in combination with levodopa/carbidopa (1/1 times the MRHD on a mg/m(2) basis) throughout the period of organogenesis (Prod Info AZILECT(R) oral tablets, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no clinical studies were available to assess the potential effects of exposure to selegiline or rasagiline during pregnancy in humans (Prod Info AZILECT(R) oral tablets, 2009; Prod Info selegiline HCl oral tablets, 2009; Prod Info ELDEPRYL(R) oral capsules, 2012; Prod Info ZELAPAR(R) oral disintegrating tablets, 2014; Prod Info EMSAM(R) transdermal system, 2014).
    B) PREGNANCY CATEGORY
    1) The manufacturers have classified selegiline and rasagiline as FDA pregnancy category C (Prod Info selegiline HCl oral tablets, 2009; Prod Info ELDEPRYL(R) oral capsules, 2012; Prod Info ZELAPAR(R) oral disintegrating tablets, 2014; Prod Info EMSAM(R) transdermal system, 2014; Prod Info AZILECT(R) oral tablets, 2009).
    2) A prospective longitudinal study in 201 pregnant women with a history of major depression found that women who discontinued their antidepressant during pregnancy had a significant increase in major depression relapse compared with those who remained on their antidepressant throughout pregnancy. Therefore, it is recommended that both the potential risks of taking an MAOI during pregnancy and the established benefits of treating depression with an antidepressant be considered (Prod Info EMSAM(R) transdermal system, 2014).
    C) LACK OF EFFECT
    1) SELEGILINE
    a) CASE REPORT: A 39-year-old woman with Parkinson disease who gave birth to a healthy male infant while continuing to take selegiline 10 mg/day (against medical advice) during her pregnancy. Her other medications included levodopa/benserazide. The child was followed over a 10-year period and his somatic and mental development were normal (Kupsch & Oertel, 1998).
    D) ANIMAL STUDIES
    1) SELEGILINE ORAL
    a) RATS: Oral selegiline doses of 36 mg/kg (no-effect dose equals12 mg/kg) produced a decrease in fetal weight. An increase in malformations was not seen (Prod Info ZELAPAR(R) orally disintegrating tablets, 2008). Rats given oral selegiline in doses of 4, 16, and 64 mg/kg (4, 15, and 62 times the human therapeutic dose on an mg/m(2) basis) showed decreases in pup survival, pup body weight (at birth as well as throughout lactation), the number of pups born per mother, and an increase in stillborn pups following the 2 highest doses. At doses of 64 mg/kg, all pups died before reaching day 4 postpartum (Prod Info ELDEPRYL(R) oral capsules, 2012; Prod Info selegiline HCl oral tablets, 2009). Rats given oral doses of 0.3, 1 (about 4 times the maximum recommended human dose [MRDH] on a mg/m(2) basis), and 10 mg/kg/day during gestation and lactation showed decreases in pup survival and pup body weights after the use of 10 mg/kg/day dose. Rats given oral doses of 5 (about 20 times the MRDH on a mg/m(2) basis), 10, and 40 mg/kg/day throughout organogenesis showed a decrease in fetal body weight after 10 and 40 mg/kg/day doses (Prod Info ZELAPAR(R) oral disintegrating tablets, 2014).
    b) RABBITS: Increases in total resorptions and postimplantation loss and a decrease in the number of live fetuses were reported at oral doses of 50 mg/kg in rabbits (no effect dose equals 25 mg/kg) (Prod Info ZELAPAR(R) orally disintegrating tablets, 2008). Embryolethality was observed in rabbits administered oral doses of 60 mg/kg and reduced fetal body weights occurred with 30- and 60-mg/kg/day doses given throughout organogenesis. No embryofetal developmental toxicity was observed following selegiline 5 mg/kg/day dose (about 40 times the MRHD on a mg/m(2) (Prod Info ZELAPAR(R) oral disintegrating tablets, 2014).
    2) SELEGILINE TRANSDERMAL
    a) RATS: Decreased fetal weight and embryofetal postimplantation lethality were reported at the highest dose when pregnant rats were given transdermal selegiline 10, 30, and 75 mg/kg/day (8, 24, and 60 times the maximum recommended human dose (MRHD) of 12 mg/24 hours on a mg/m(2) basis) during the period of organogenesis. Concentrations of selegiline and its metabolites were similar in fetal and maternal plasma. In another study in which rats were given the same doses transdermally (10, 30, and 75 mg/kg/day) on days 6 through 21 of gestation, an increase in stillborn pups and decreased implantations and litter size were reported at the high dose. Increased postimplantation loss and retarded pup physical development were reported at the 30 and 75-mg/kg doses. Retarded neurobehavioral and sexual development were reported at all doses (Prod Info EMSAM(R) transdermal system, 2014).
    3) RASAGILINE
    a) RATS: No effect on embryo-fetal development was observed at doses up to 3 mg/kg/day (approximately 30 times the expected plasma rasagiline exposure (AUC) at the maximum recommended human dose (MRHD) of 1 mg/day) in a study of female rats (Prod Info AZILECT(R) oral tablets, 2009).
    b) RATS: Decreased offspring survival and reduced offspring body weight were reported when pregnant rats were given oral rasagiline at doses of 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the expected plasma rasagiline exposure AUC at the MRHD) at the beginning of organogenesis to day 20 postpartum. No effects were observed at a dose of 0.1 mg/kg/day (1 time the MRHD on a mg/m(2) basis) (Prod Info AZILECT(R) oral tablets, 2009).
    c) RABBITS: Increased embryo-fetal death was reported when pregnant rabbits were given rasagiline at doses of 0.6 and 1.2 mg/kg/day (approximately 7 and 13 times the plasma rasagiline AUC at the MRHD) in combination with levodopa/carbidopa at 80/20 mg/kg/day throughout the period of organogenesis (Prod Info AZILECT(R) oral tablets, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) SELEGILINE: In an animal study, decreases in pup weight (throughout lactation and postweaning periods) and survival (throughout lactation period) were reported at the mid and high doses when rats were given transdermal doses of 10, 30, and 75 mg/kg/day (8, 24, and 60 times the maximum recommended human dose of 12 mg/24 hours on a mg/m(2) basis) on days 6 through 21 of gestation and days 1 through 21 of the lactation period. Concentrations of selegiline and its metabolites in rat milk were approximately 15 and 5 times, respectively, that found in maternal plasma which indicated direct dosing of pups during lactation (Prod Info EMSAM(R) transdermal system, 2014).
    2) SELEGILINE: It is unknown whether selegiline is excreted in human milk. In animal studies, selegiline was excreted into the milk of lactating rats and concentrations of selegiline and its metabolites were higher in milk than those in maternal plasma (Prod Info ZELAPAR(R) oral disintegrating tablets, 2014; Prod Info EMSAM(R) transdermal system, 2014). Because data are lacking and many drugs are excreted into human milk, exercise caution when administering selegiline to a nursing mother (Prod Info selegiline HCl oral tablets, 2009; Prod Info ELDEPRYL(R) oral capsules, 2012; Prod Info ZELAPAR(R) oral disintegrating tablets, 2014). Due to the potential for serious adverse effects in nursing infants exposed to selegiline, it is recommended to either discontinue nursing or selegiline, considering the importance of the drug to the mother (Prod Info EMSAM(R) transdermal system, 2014)
    3) RASAGILINE: Rasagiline inhibits prolactin secretion in rats, and may inhibit milk secretion in females. Data regarding use in lactating women are not available. Caution should be exercised when rasagiline is administered to a lactating woman (Prod Info AZILECT(R) oral tablets, 2006).
    B) ANIMAL STUDIES
    1) SELEGILINE
    a) RATS: Concentrations of selegiline and its metabolites were approximately 15 and 5 times, respectively, that found in plasma which indicated direct dosing of pups during lactation (Prod Info EMSAM(R) transdermal system, 2014).
    2) RASAGILINE
    a) RATS: In rat studies, rasagiline inhibited prolactin secretion, which may inhibit milk production (Prod Info AZILECT(R) oral tablets, 2006).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to selegiline or rasagiline in humans (Prod Info ZELAPAR(R) oral disintegrating tablets, 2014; Prod Info ELDEPRYL(R) oral capsules, 2012; Prod Info AZILECT(R) oral tablets, 2006).
    B) ANIMAL STUDIES
    1) SELEGILINE ORAL
    a) RATS: Decreased number of implantations in female rats were reported with oral doses of selegiline at 25 mg/kg/day given before mating, during mating, and continuing to gestation day 7. Reduced sperm density and sperm counts in male rats were reported with oral doses of selegiline at 40 mg/kg/day before and during mating (Prod Info ZELAPAR(R) oral disintegrating tablets, 2014).
    2) SELEGILINE TRANSDERMAL
    a) RATS: Slight decreases in sperm concentration and total sperm count were reported when male rats were given transdermal selegiline at doses of 75 mg/kg/day (60 times the maximum recommended human dose of 12 mg/24 hours on a mg/m(2) basis). No significant adverse effects on fertility or reproductive performance were observed in the male rats or in female rats receiving the same doses (Prod Info EMSAM(R) transdermal system, 2014).
    3) RASAGILINE
    a) No effect on mating performance or fertility was observed when oral rasagiline was given to male rats (treatment period prior to and throughout the mating period) and female rats (treatment period prior to mating through day 17 of gestation) at doses of 3 mg/kg/day (approximately 30 times the expected plasma rasagiline exposure (AUC) at the maximum recommended human dose of 1 mg/day) (Prod Info AZILECT(R) oral tablets, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) MAO-BI plasma concentrations are not clinically useful or readily available.
    C) Screening urine toxicology immunoassays will not detect MAOIs. Selegiline is converted to amphetamine which may be detected on a urine toxicology screen.
    D) In symptomatic patients, obtain a basic chemistry profile, lactate, CPK, ECG, renal function, and coagulation panel. Obtain cardiac enzymes in a patient with chest pain.
    E) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection in a patient with an altered mental status.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) SELEGILINE: Abbott TDx can detect the l-methamphetamine and l-amphetamine metabolites of selegiline in urine (Meeker & Reynolds, 1990).
    a) Roche Abuscreen did not detect l-methamphetamine or l-amphetamine in urine or blood; it is specific for d-methamphetamine with very little cross reactivity (Meeker & Reynolds, 1990).
    B) GC/MS
    1) SELEGILINE METABOLISM: An adult taking selegiline had a borderline positive methamphetamine RIA screening test, while a GC/MS study showed 4690 ng/mL of methamphetamine and 1895 ng/mL of amphetamine. Because selegiline metabolizes to amphetamine or methamphetamine careful interpretation of test results is indicated to avoid misinterpretation (ie, intentional drug abuse) (Romberg et al, 1995).
    a) Further study indicated that the urinary [Amphetamine]/[Methamphetamine] ratios after selegiline use ranged from 0.13 to 0.3 during the first 24 hours, from 0.15 to 0.41 for 24 to 48 hours and from 0.27 to 0.81 for 48 to 72 hours. Following 1-methamphetamine (eg, a Vicks inhaler) use, the ratio was less than 0.1 for the first 24 hours. Findings indicate that [Amp]/[Met] ratios are consistently higher from selegiline users as compared to 1-methamphetamine users. This testing may be useful in distinguishing between selegiline and 1-methamphetamine use (Romberg et al, 1995).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant persistent hypertension, tachycardia or central nervous depression should be admitted to the hospital. Patients with coma, seizures, dysrhythmias, hyperthermia, or delirium should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children should be evaluated in the hospital and observed. Adults should be evaluated by a health care professional if they have received a higher than therapeutic dose, or if they are symptomatic.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions or children with inadvertent ingestions should be sent to a health care facility for observation for 6 to 8 hours.

Monitoring

    A) Monitor vital signs and mental status.
    B) MAO-BI plasma concentrations are not clinically useful or readily available.
    C) Screening urine toxicology immunoassays will not detect MAOIs. Selegiline is converted to amphetamine which may be detected on a urine toxicology screen.
    D) In symptomatic patients, obtain a basic chemistry profile, lactate, CPK, ECG, renal function, and coagulation panel. Obtain cardiac enzymes in a patient with chest pain.
    E) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection in a patient with an altered mental status.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY: As MAO-BI overdoses are generally not serious, there is no role for prehospital decontamination following oral exposure. Search for and remove any transdermal patches on the patient's body. Patches are often under clothing and can be found on the back, chest or upper arm.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Consider decontamination if a patient presents shortly (eg, within 1 to 2 hours) after a large oral ingestion overdose and is not manifesting symptoms of toxicity. Activated charcoal is generally not recommended in patients that are manifesting signs of toxicity as they may become comatose or seize and lose their airways. If the airway is protected with orotracheal intubation, charcoal may be given. However, it is still possible that patients may aspirate around the endotracheal tube. Whole bowel irrigation should be considered if there is a clear ingestion of a transdermal preparation. Gastric lavage is not indicated as serious toxicity is rare.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    C) WHOLE BOWEL LAVAGE
    a) WHOLE BOWEL IRRIGATION/INDICATIONS: Whole bowel irrigation with a polyethylene glycol balanced electrolyte solution appears to be a safe means of gastrointestinal decontamination. It is particularly useful when sustained release or enteric coated formulations, substances not adsorbed by activated charcoal, or substances known to form concretions or bezoars are involved in the overdose.
    1) Volunteer studies have shown significant decreases in the bioavailability of ingested drugs after whole bowel irrigation (Tenenbein et al, 1987; Kirshenbaum et al, 1989; Smith et al, 1991). There are no controlled clinical trials evaluating the efficacy of whole bowel irrigation in overdose.
    b) CONTRAINDICATIONS: This procedure should not be used in patients who are currently or are at risk for rapidly becoming obtunded, comatose, or seizing until the airway is secured by endotracheal intubation. Whole bowel irrigation should not be used in patients with bowel obstruction, bowel perforation, megacolon, ileus, uncontrolled vomiting, significant gastrointestinal bleeding, hemodynamic instability or inability to protect the airway (Tenenbein et al, 1987).
    c) ADMINISTRATION: Polyethylene glycol balanced electrolyte solution (e.g. Colyte(R), Golytely(R)) is taken orally or by nasogastric tube. The patient should be seated and/or the head of the bed elevated to at least a 45 degree angle (Tenenbein et al, 1987). Optimum dose not established. ADULT: 2 liters initially followed by 1.5 to 2 liters per hour. CHILDREN 6 to 12 years: 1000 milliliters/hour. CHILDREN 9 months to 6 years: 500 milliliters/hour. Continue until rectal effluent is clear and there is no radiographic evidence of toxin in the gastrointestinal tract.
    d) ADVERSE EFFECTS: Include nausea, vomiting, abdominal cramping, and bloating. Fluid and electrolyte status should be monitored, although severe fluid and electrolyte abnormalities have not been reported, minor electrolyte abnormalities may develop. Prolonged periods of irrigation may produce a mild metabolic acidosis. Patients with compromised airway protection are at risk for aspiration.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) MAO-BI plasma concentrations are not clinically useful or readily available.
    3) Screening urine toxicology immunoassays will not detect MAOIs. Selegiline is converted to amphetamine which may be detected on a urine toxicology screen.
    4) In symptomatic patients, obtain a basic chemistry profile, lactate, CPK, ECG, renal function, and coagulation panel. Obtain cardiac enzymes in patients with chest pain.
    5) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection in patients with altered mental status.
    B) HYPOTENSIVE EPISODE
    1) Postural hypotension has been reported with MAO-B Inhibitors during therapeutic use.
    2) Administer intravenous fluids, place in Trendelenburg position. If the patient is unresponsive to these measures, administer norepinephrine or dopamine cautiously, monitoring for possible exaggerated response.
    a) The direct-acting alpha-adrenergic agonist norepinephrine (levarterenol) may be preferable since it does not require release of intracellular amines (Linden et al, 1984).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    4) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    C) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).
    D) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    E) HYPERTENSIVE EPISODE
    1) Symptomatic hypertension is best treated with the rapid, short-acting parenteral alpha-adrenergic blocker phentolamine, or by the direct vasodilator sodium nitroprusside (Guzzardi, 1983). Methyldopa and guanethidine are contraindicated as they may potentiate hypertensive crises.
    2) IV NITROPRUSSIDE (ADULT and CHILD: Initially 1 microgram/kilogram/minute by intravenous infusion; titrate up to 10 micrograms/kilogram/minute as needed to achieve desired effect) or PHENTOLAMINE (ADULT: 2.5 to 5 milligrams every 5 minutes until hypertension is controlled then every 2 to 4 hours as needed; CHILD: 0.05 to 0.1 milligram/kilogram/dose every 5 minutes until hypertension is controlled then every 1 to 4 hours as needed).
    3) LABETALOL: Has been used to treat successfully one case of accelerated hypertension due to a tranylcypromine-tyramine interaction (Abrams et al, 1985).

Abstracts

Case Reports

    A) Based on surveillance data collected by the American Association of Poison Control Centers (AAPCC), 15 cases of selegiline and 1 case of rasagiline adverse events were reported during the first half of 2008. Of the 16 cases, 4 unintentional exposures occurred in children between the ages of 20 months and 9 years with minimal or no effects reported. There were 3 cases of intentional exposure in adults. One 24-year-old female with a mixed ingestion (ie, selegiline hydrochloride, carbidopa/entacapone/levodopa preparation, synthroid, and amantadine) developed no effects, while 2 other adults had possible toxic effects following mixed ingestions that included ethanol, a cold preparation (included dextromethorphan, ethanol) and a SSRI. The outcome of these 2 patients was not determined (Bronstein, 2008).

Range Of Toxicity

Summary

    A) TOXICITY: The toxic dose varies widely, depending on the specific agent. Most of MAOIs have narrow therapeutic windows. A selegiline dose of 600 mg caused hypotension and psychomotor agitation. Rasagiline 2 mg/day caused mild symptoms in healthy adults. Patients on chronic levodopa therapy developed hypertension and orthostatic hypotension with 10 g rasagiline.

Therapeutic Dose

    7.2.1) ADULT
    A) SELEGILINE
    1) ORAL DISINTEGRATING: INITIAL DOSE: 1.25 mg given once daily for at least 6 weeks; the dose may be increased to 2.5 mg give once day if the desired effect has not been achieved. Maximum: 2.5 mg daily (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006).
    2) SELEGILINE HYDROCHLORIDE: ORAL TABLET OR CAPSULE: 10 mg daily in divided doses of 5 mg each taken at breakfast and lunch for the treatment of Parkinson's disease. No evidence exists that higher doses provide any additional benefit (Prod Info selegiline hcl oral tablets, 2003; Prod Info ELDEPRYL(R) oral capsules, 1998).
    3) TRANSDERMAL PATCH: 6 mg/24 hours (20 mg/20 cm(2)) patch topically every 24 hours; may increase at increments of 3 mg/24 hours at intervals of no less than 2 weeks up to 12 mg/24 hours (Prod Info EMSAM(R) transdermal system, 2014)
    B) RASAGILINE
    1) ADJUNCT THERAPY WITHOUT LEVODOPA: The recommended dose is 1 mg administered orally once daily (Prod Info AZILECT(R) oral tablets, 2014).
    2) CONCOMITANT LEVODOPA WITH OR WITHOUT OTHER PARKINSON'S DISEASE DRUGS: The recommended dose is 0.5 mg once daily. Dose may be increased to 1 mg/day (Prod Info AZILECT(R) oral tablets, 2014).
    3) MONOTHERAPY: The recommended dose is 1 mg administered orally once daily (Prod Info AZILECT(R) oral tablets, 2014)
    7.2.2) PEDIATRIC
    A) SELEGILINE
    1) ORAL DISINTEGRATING:
    a) The safety and efficacy have not been studied in pediatric patients (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006).
    2) TRANSDERMAL PATCH
    a) YOUNGER THAN 12 YEARS OF AGE: The safety and efficacy have not been established. Use is contraindicated in children under 12 years of age (Prod Info AZILECT(R) oral tablets, 2014)
    b) ADOLESCENTS 12 TO 17 YEARS OF AGE: In a 12-week, multi-center, randomized, double-blind, placebo-controlled, flexible dose trial, transdermal selegiline 6 mg/24 hours, 9 mg/24 hours, or 12 mg/24 hours did not demonstrate efficacy when administered to adolescents (n=308; age range, 12 to 17 years) with major depressive disorder. Safety findings in adolescents were similar to safety findings in adult trials (Prod Info AZILECT(R) oral tablets, 2014).
    B) RASAGILINE
    1) The safety and efficacy of these agents have not been studied in pediatric patients (Prod Info AZILECT(R) oral tablets, 2014).

Minimum Lethal Exposure

    A) At the time of this review, a minimum lethal dose has not been established.

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) SELEGILINE: Doses of 600 mg, l-selegiline have resulted in hypotension and psychomotor agitation (Prod Info selegiline hcl oral tablets, 2003).
    2) COMBINATION OVERDOSE: CASE REPORT: A 50-year-old man with a medical history of bipolar II disorder, developed coma, generalized seizures, visual hallucinations, and hypertension as high as 170/110 mmHg after ingesting 195 mg of selegiline, 8600 mg of carbamazepine, 16,000 mg of sodium valproate (sustained-release preparation), 2250 mg of trazodone, and 70 mg of nitrazepam. Following supportive care, he gradually recovered (Kobayashi et al, 2011).
    3) RASAGILINE: In clinical trials with healthy volunteers, rasagiline was well tolerated producing only mild or moderate symptoms following a single-dose study of 20 mg/day and in a 10-day study receiving 10 mg/day. Three patients on chronic levodopa therapy experienced cardiovascular effects (ie, hypertension and postural hypotension) in a dose escalation study that were also treated with 10 mg of rasagiline; symptoms resolved with drug discontinuation (Prod Info AZILECT(R) oral tablets, 2006).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SELEGILINE - Methamphetamine and amphetamine were detected in femoral blood, heart blood, urine, and liver in a 72-year-old female who died of a suspected drug overdose. She had prescriptions in her residence for selegiline, desipramine, trazodone, bromocriptine, and naproxen (Meeker & Reynolds, 1990).
    a) The following values were observed:
    DRUGHEART BLOOD CONCENTRATION
    Methamphetamine0.28 mcg/mL
    Amphetamine0.08 mcg/mL
    Methyprylon6.8 mcg/mL
    Nortriptyline2.36 mcg/mL
    Trazodone0.05 mcg/mL
    Ethanol0.07%

Pharmacology Toxicology

Pharmacologic Mechanism

    A) RASAGILINE
    1) Rasagiline (N-propargyl-1R(+)-aminoindan; TVP-1012) is a selective and irreversible inhibitor of monoamine oxidase type B (MAO-B), with structural similarity to selegiline (Youdim et al, 2001; Finberg & Youdim, 2002; Maruyama et al, 2001). It is the R(+)-enantiomer of the N-propargyl-1-aminoindan AGN-1135 (Maruyama et al, 2001). Rasagiline is approximately 100-fold more potent as an inhibitor of MAO-B compared to MAO-A; it is substantially more potent (3800-fold) than the S(-)-enantiomer (TVP-1022) with respect to MAO-B inhibition (Youdim et al, 2001).
    2) In contrast to selegiline, rasagiline does not appear to be metabolized to amphetamine derivatives (eg, l-methamphetamine), but rather to aminoindan compounds (Mandel et al, 2005; Youdim et al, 2001a; Mealy et al, 2002). The potency of rasagiline and selegiline is similar for inhibition of MAO-B in vitro, whereas rasagiline has been demonstrated to be 3 to 15 times more potent as an inhibitor in vivo (Youdim et al, 2001; Youdim et al, 2001a). Inhibition curves for MAO-B have been similar in liver and brain (Youdim et al, 2001). The mechanism for greater MAO-B-inhibitory potency relative to selegiline in vivo may be related to better tissue penetration of rasagiline (Youdim et al, 2001) or slower metabolism.
    3) Similar to selegiline, rasagiline appears to possess neuroprotective and antiapoptotic properties, unrelated to MAO-B inhibition (Maruyama et al, 2001; Youdim et al, 2001a; Weinstock et al, 2001). In animal models, rasagiline exhibited neuroprotective effects in closed-head injury, and prevented and at least partially reversed neurotoxicity induced by alpha-methyl-para-tyrosine (Youdim et al, 2001a). Inhibition of death-signal transduction in mitochondria has been postulated as a mechanism for neuroprotective effects (Akao et al, 2002), although others have also been suggested.
    4) Rasagiline does not appear to potentiate sympathomimetic effects of tyramine (ie, cheese reaction) (Youdim et al, 2001a; Youdim et al, 2001).
    B) SELEGILINE
    1) BACKGROUND - Selegiline is a phenylalkylamine that resembles amphetamine in structure. Chemically, the drug is N-methyl-N-(1-phenylpropan-2-yl)prop-2-yn-1-amine, and the levorotatory isomer (l or (-)) is clinically active (Bianchine, 1985; Sandler, 1983). It is a monoamine oxidase inhibitor with specificity for one of the monoamine oxidase (MAO) isozymes, MAO-B. The MAO enzyme exists in 2 forms, MAO-A and MAO-B (Pickar et al, 1982; Murphy et al, 1984; Riederer & Jellinger, 1983; Denney & Denney, 1985). The distinction between the 2 types of MAO is based on substrate specificities observed in vitro (Squires, 1972). Serotonin and/or epinephrine have a high affinity for the MAO-A isoenzyme, whereas, phenylethylamine (PEA), telemethylhistamine, and dopamine have a high affinity for the MAO-B isoenzyme. Tyramine is an equally good substrate for both enzyme forms (Pickar et al, 1981; Linnoila et al, 1982; Glover et al, 1977). Although tyramine is a substrate for both MAO-A and MAO-B isozymes, the administration of tyramine in amounts greater than normally ingested (200 mg) does not produce a hypertensive reaction in patients who receive selegiline chronically at doses less than 30 mg/day (no cheese effect) (Elsworth et al, 1978). MAO-B selectivity is lost at doses greater than 30 mg/day (Golbe et al, 1988).
    2) ACTION - The action of selegiline is thought to be related to its irreversible (Golbe, 1988) inhibition of monoamine oxidase, with greater affinity for type B (MAO B) (Prod Info EMSAM(R) transdermal patch, 2006; Anon, 1989), the major form of the enzyme in the human brain (Sonsalla & Golbe, 1988; Golbe, 1988). MAO B, which is involved in the oxidative deamination (Witt, 1986; Golbe, 1988a) of dopamine in the brain (Anon, 1989), is inhibited when selegiline binds covalently (Youdim & Finberg, 1986; Golbe, 1988) and stoichiometrically (Youdim & Finberg, 1986) to the isoalloxazine (Youdim & Finberg, 1986) flavin adenine dinucleotide (FAD) (Youdim & Finberg, 1986; Golbe, 1988) at its active center (Youdim & Finberg, 1986). Administration of 10 mg of selegiline a day orally (Yahr, 1987; Witt, 1986; Tetrud & Langston, 1989) produces almost complete inhibition of MAO B (Yahr, 1987; Witt, 1986) in the brain (Witt, 1986; Tetrud & Langston, 1989; Golbe, 1988). Selegiline becomes a nonselective inhibitor of both monoamine oxidase A (MAO-A) and MAO-B at higher doses used for antidepressant activity (Prod Info EMSAM(R) transdermal patch, 2006; Witt, 1986; Sonsalla & Golbe, 1988; Golbe, 1988a), possibly at 20 to 40 mg a day orally and at the 9 mg/24 h and 12 mg/24 h transdermal patch (Prod Info EMSAM(R) transdermal patch, 2006; Witt, 1986; Golbe, 1988a; Panelist comments, 1/90.). At these doses, tyramine-mediated hypertensive reactions from MAO A blockade (cheese reactions) may occur (Robinson & Amsterdam, 2008; Prod Info EMSAM(R) transdermal patch, 2006; Witt, 1986).
    3) Selegiline (or its metabolites) may also act through other mechanisms to increase dopaminergic activity (Prod Info Eldepryl, 89; Csanda & Tarczy, 1987), including interfering with dopamine reuptake (Witt, 1986; Karoum, 1982) at the synapse.
    4) Although selegiline is metabolized to amphetamine and methamphetamine, it is not clear whether these metabolites contribute to the efficacy of the drug (Reynolds et al, 1978; Schachter et al, 1980; Karoum et al, 1982).
    5) Parkinsonian patients treated with selegiline had significantly more intact neurons in the substantia nigra than those treated without it. In addition, significantly fewer Lewy bodies (relative to the number of intact neurons) were found in the selegiline-treated patients. These results suggest a possible neuroprotective effect of selegiline in Parkinson's disease(Rinne et al, 1991). Selegiline has been shown to postpone the need for levodopa in patients with early PD, due in part to its symptomatic effects and its usefulness in the management of motor fluctuations in more advanced disease (Youdim & Riederer, 2004).
    C) SELEGILINE HYDROCHLORIDE
    1) Selegiline hydrochloride is a levorotatory acetylenic derivative of phenethylamine and a selective type B monoamine oxidase (MAO) inhibitor. It acts as a suicide substrate wherein MAO transforms it into an active moiety which irreversibly binds with the active site and/or the important flavin-adenine dinucleotide (FAD) cofactor of the enzyme, thereby blocking MAO activity. It may also elevate dopaminergic activity by inhibiting the re-uptake of dopamine at the synapse (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006; Prod Info selegiline hydrochloride oral tablet, USP, 2003; Prod Info ELDEPRYL(R) oral capsule, 1998).

Toxicologic Mechanism

    A) As the dose of a MAO-B inhibitor is increased, selectivity may be lost. Although there are no reports of SEVERE effects in overdose, in theory clinical effects (eg, cardiac events, seizures, coma, respiratory depression, hyperpyrexia, hallucinations) may appear similar to non-selective MAO inhibitors after large overdose of MAO B inhibitors (Prod Info AZILECT(R) oral tablets, 2006; Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006; Prod Info EMSAM(R) transdermal patch, 2006).
    B) Selective MAO inhibitors such as selegiline, which inhibits only MAO-B, do not appear to interact with tyramine at recommended doses (ie, 10 mg/day). However, at dosages above 30 to 40 mg/day or following an overdose, non-selective MAO inhibition might occur; therefore, dietary restrictions of tyramine are necessary for several weeks to avoid any risk of hypertensive/cheese reaction (Prod Info ZELAPAR(TM) orally disintegrating tablets, 2006; Lieberman et al, 1985).

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