Selegiline

Avoid drinking alcohol while you are taking selegiline.

While taking selegiline and for 14 days after you stop, you must NOT eat foods that are high in tyramine, including:

• air dried meats, aged or fermented meats, sausage or salami (including cacciatore and mortadella), pickled herring;
• any spoiled or improperly stored beef, poultry, fish, or liver;
• beer from a tap, beer that has not been pasteurized;
• aged cheeses (such as blue, Swiss, cheddar, Parmesan, or Romano cheese);
• over-the-counter supplements or cough and cold medicines that contain tyramine;
• sauerkraut, soy beans, soy sauce, tofu, fava beans; or
• yeast extracts (such as Marmite).

Eating tyramine while you are using selegiline can raise your blood pressure to dangerous levels which could cause life-threatening side effects. You should become very familiar with the list of foods to avoid while you are using selegiline.

Selegiline may impair your thinking or reactions. Some people taking this medicine have fallen asleep during normal daytime activities such as working, talking, eating, or driving. You may fall asleep suddenly, even after feeling alert. Be careful if you drive or do anything that requires you to be alert.

While using the 9-mg or 12-mg patches, and for 14 days after you stop, you must NOT eat foods that are high in tyramine, including:

• air dried meats, aged or fermented meats, sausage or salami (including cacciatore and mortadella), pickled herring, and any spoiled or improperly stored beef, poultry, fish, or liver;
• beer from a tap, beer that has not been pasteurized;
• aged cheeses (such as blue, Swiss, cheddar, Parmesan, or Romano cheese);
• over-the-counter supplements or cough and cold medicines that contain tyramine;
• sauerkraut, soy beans, soy sauce, tofu, fava beans; or
• yeast extracts (such as Marmite).

Eating tyramine while you are using selegiline can raise your blood pressure to dangerous levels which could cause life-threatening side effects. You should become very familiar with the list of foods to avoid while you are using selegiline.

Avoid drinking alcohol while you are using selegiline.

This medicine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Many drugs can interact with selegiline, and some drugs should not be used together. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with selegiline. Give a list of all your medicines to any healthcare provider who treats you.

There are many other medicines that can cause serious medical problems if you take them while using selegiline. Tell your doctor about all your current medicines and any you start or stop using, especially:

• buspirone (BuSpar);
• any other antidepressant;
• cough or cold medicine that contains a decongestant such as phenylephrine or pseudoephedrine;
• prescription or over-the-counter diet pills;
• an herbal or dietary supplement that contains tyramine; or
• stimulant medicine such as Adderall or other medicines to treat attention deficit hyperactivity disorder (ADHD).

This list is not complete and many other drugs can interact with selegiline. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Give a list of all your medicines to any healthcare provider who treats you.

Selegiline is used to help control the symptoms of Parkinson's disease, and the patch form is used to treat depression in adults. Selegiline belongs to a group of drugs called monamine oxidase (MAO) inhibitors, which affect levels of certain natural substances in the brain. These substances are involved with motor control and also mental balance.

This medication comes in tablet and capsule forms. They are taken twice daily, one dose at breakfast and the second dose at lunch.

This medication is also available as an orally disintegrating tablet. It is taken in the morning before breakfast and without liquid.

This medication additionally comes in the form of a skin patch. It is applied once a day to the upper chest or back, upper thigh, or upper arm.

Common side effects of selegiline include redness in the application area, a large and sudden increase in blood pressure (hypertensive crisis), and low blood pressure (hypotension).  Do not drive or operate machinery until you know how selegiline will affect you.

Selegiline is part of the drug class:

• Monoamine oxidase B inhibitors

Oral/Topical:

• Selegiline can cause a sudden, large increase in blood pressure (‘‘hypertensive crisis’’) if you eat certain foods and drinks during treatment. See “Drug Precautions”. A hypertensive crisis can lead to stroke and death. Symptoms of a hypertensive crisis include the sudden onset of severe headache, nausea, stiff neck, a fast heartbeat or a change in the way your heart beats (palpitations), a lot of sweating, and confusion. If you suddenly have these symptoms, get medical care right away.
• Selegiline can cause serious and potentially life-threatening reactions if used with certain other medicines. See “Selegiline Drug Precautions”.
• Selegiline may worsen your depression, give you suicidal thoughts, or cause unusual changes in behavior.  Call your doctor right away if you feel worse with selegiline.
• Selegiline may cause a mental condition called mania or hypomania (mental condition which causes high moods) in people who have a history of mania.
• Selegiline can cause low blood pressure. Lie down if you feel dizzy, faint, or lightheaded. Change your position slowly if low blood pressure is a problem for you. Tell your doctor if you have these symptoms. You may need a lower dose of selegiline.

Oral:

The most common side effects with selegiline include the following dizziness, nausea, pain, headache, insomnia, runny nose, involuntary movement, back pain, mouth inflammation, and upset stomach.

Topical:

The most common side effect of selegiline is a skin reaction where the patch is placed. You may see mild redness at the site when a patch is removed. This redness should go away within several hours after removing the patch. If irritation or itching continues, tell your doctor.

These are not all the side effects of selegiline. For more information, ask your doctor or pharmacist.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

If you take too much this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

General

Some patients given Selegiline may experience an exacerbation of levodopa associated side effects, presumably due to the increased amounts of dopamine reaction with super sensitive, post-synaptic receptors. These effects may often be mitigated by reducing the dose of levodopa/carbidopa by approximately 10 to 30%.

The decision to prescribe Selegiline should take into consideration that the MAO system of enzymes is complex and incompletely understood and there is only a limited amount of carefully documented clinical experience with Selegiline. Consequently, the full spectrum of possible responses to Selegiline may not have been observed in pre-marketing evaluation of the drug. It is advisable, therefore, to observe patients closely for atypical responses.

Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Selegiline for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Information for Patients

Patients should be advised of the possible need to reduce levodopa dosage after the initiation of Selegiline therapy.

Patients (or their families if the patient is incompetent) should be advised not to exceed the daily recommended dose of 10 mg. The risk of using higher daily doses of Selegiline should be explained, and a brief description of the `cheese reaction' provided. Rare hypertensive reactions with Selegiline at recommended doses associated with dietary influences have been reported.

Consequently, it may be useful to inform patients (or their families) about the signs and symptoms associated with MAOI induced hypertensive reactions. In particular, patients should be urged to report, immediately, any severe headache or other atypical or unusual symptoms not previously experienced.

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease, including Selegiline. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Selegiline. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Selegiline. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Selegiline.

Laboratory Tests

No specific laboratory tests are deemed essential for the management of patients on Selegiline. Periodic routine evaluation of all patients, however, is appropriate.

Drug Interactions

The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of Selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination (see CONTRAINDICATIONS). Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and Selegiline and selective serotonin reuptake inhibitors and Selegiline. (See WARNINGS for details.) One case of hypertensive crisis has been reported in a patient taking the recommended doses of Selegiline and a sympathomimetic medication (ephedrine).

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Assessment of the carcinogenic potential of Selegiline in mice and rats is ongoing.

Selegiline did not induce mutations or chromosomal damage when tested in the bacterial mutation assay in Salmonella typhimurium and in an in vivo chromosomal aberration assay. While these studies provide some reassurance that Selegiline is not mutagenic or clastogenic, they are not definitive because of methodological limitations. No definitive in vitro chromosomal aberration or in vitro mammalian gene mutation assays have been performed.

The effect of Selegiline on fertility has not been adequately assessed.

Pregnancy

No teratogenic effects were observed in a study of embryo-fetal development in Sprague-Dawley rats at oral doses of 4, 12, and 36 mg/kg or 4, 12 and 35 times the human therapeutic dose on a mg/m2 basis. No teratogenic effects were observed in a study of embryo-fetal development in New Zealand White rabbits at oral doses of 5, 25, and 50 mg/kg or 10, 48, and 95 times the human therapeutic dose on a mg/m2 basis; however, in this study, the number of litters produced at the two higher doses was less than recommended for assessing teratogenic potential. In the rat study, there was a decrease in fetal body weight at the highest dose tested. In the rabbit study, increases in total resorptions and % post-implantation loss, and a decrease in the number of live fetuses per dam occurred at the highest dose tested. In a peri- and postnatal development study in Sprague-Dawley rats (oral doses of 4, 16, and 64 mg/kg or 4, 15, and 62 times the human therapeutic dose on a mg/m2 basis), an increase in the number of stillbirths and decreases in the number of pups per dam, pup survival, and pup body weight (at birth and throughout the lactation period) were observed at the two highest doses. At the highest dose tested, no pups born alive survived to Day 4 postpartum. Postnatal development at the highest dose tested in dams could not be evaluated because of the lack of surviving pups. The reproductive performance of the untreated offspring was not assessed.

There are no adequate and well-controlled studies in pregnant women. Selegiline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether Selegiline hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, consideration should be given to discontinuing the use of all but absolutely essential drug treatments in nursing women.

Pediatric Use

The effects of Selegiline hydrochloride in children have not been evaluated.

Selegiline hydrochloride capsules are intended for administration to Parkinsonian patients receiving levodopa/carbidopa therapy who demonstrate a deteriorating response to this treatment. The recommended regimen for the administration of Selegiline hydrochloride is 10 mg per day administered as divided doses of 5 mg each taken at breakfast and lunch. There is no evidence that additional benefit will be obtained from the administration of higher doses. Moreover, higher doses should ordinarily be avoided because of the increased risk of side effects.

After two to three days of Selegiline treatment, an attempt may be made to reduce the dose of levodopa/carbidopa. A reduction of 10 to 30% was achieved with the typical participant in the domestic placebo controlled trials who was assigned to Selegiline treatment. Further reductions of levodopa/carbidopa may be possible during continued Selegiline therapy.

Potent, irreversible inhibitor of monoamine oxidase (MAO). Plasma concentrations achieved via administration of oral dosage forms in recommended doses confer selective inhibition of MAO type B, which plays a major role in the metabolism of dopamine, serotonin, norepinephrine, and epinephrine in the CNS; selegiline may also increase dopaminergic activity by interfering with dopamine reuptake at the synapse. When administered transdermally in recommended doses, selegiline achieves higher blood levels and effectively inhibits both MAO-A and MAO-B, an enzyme in the gut and liver that metabolizes dietary amines such as tyramine.

Absorption

Capsule/tablet: Bioavailability increases 3- to 4-fold when taken with food

Orally disintegrating tablet: Rapid; greater bioavailability than capsule/tablet. Food decreases Cmax and AUC to ~60% of fasting state.

Transdermal: 25% to 30% (of total selegiline content) over 24 hours

Metabolism

Hepatic, primarily via CYP2B6, CYP2C9, CYP3A4, and CYP2A6 (minor) to active (N-desmethylselegiline, amphetamine, methamphetamine) and inactive metabolites

Excretion

Urine (primarily metabolites); feces

Half-Life Elimination

Oral: 10 hours

Protein Binding

Protein binding: 85% to 90%

Systemic exposure is about twice as high in elderly patients when given a single 10 mg oral dose.

Attention-deficit/hyperactivity disorder (ADHD)

Data from a controlled, double-blind study supports the use of selegiline in the treatment of attention-deficit/hyperactivity disorder (ADHD) [Akhondzadeh 2003]. Data from a randomized, double-blind study also supports the use of selegiline in the treatment of attention-deficit/hyperactivity disorder (ADHD) [Mohammadi 2004]. Additional trials may be necessary to further define the role of selegiline in this condition.

Early Parkinson's disease

Clinical experience suggests the utility of selegiline in the treatment of early Parkinson's disease [Collier 1992]. Additional trials may be necessary to further define the role of selegiline in this condition.

Hypersensitivity to selegiline or any component of the formulation; concomitant use of meperidine

Orally disintegrating tablet: Additional contraindications: Concomitant use of methadone, other MAO inhibitors (selective or non-selective), propoxyphene, or tramadol within 14 days of selegiline; concomitant use with cyclobenzaprine, dextromethorphan, or St John’s wort

Transdermal: Additional contraindications: Pheochromocytoma; patients <12 years of age; use of carbamazepine, serotonin reuptake inhibitors (including SSRIs and SNRIs), clomipramine, imipramine, tramadol, propoxyphene, methadone, pentazocine, and dextromethorphan (concurrently, within 2 weeks of selegiline discontinuation, or selegiline use within 4 to 5 half-lives [approximately 1 week for most medications; 5 weeks for fluoxetine] of discontinuation of the contraindicated drug)

Depression: Adolescents >17 years: Transdermal: Refer to adult dosing.

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Administration advice:
-Oral tablet: Doses should be taken with food, at breakfast and lunch
-Orally disintegrating tablets: Patients should avoid ingesting food or liquids for 5 minutes before and after taking a dose
-Transdermal patch: Follow the detailed instructions in the medication guide. Patches should be applied to dry intact skin on the upper torso, upper thigh, or the outer surface of the upper arm. Rotate application sites; avoid reapplication to the same site on consecutive days.

Storage requirements:
-Orally disintegrating tablet: Once opened, unused tablets must be disposed of after 3 months.

General:
-Treatment should be periodically reevaluated
-This drug interacts with other drugs; prescribers should be aware for the potential for interactions. A washout period may be required between ceasing selegiline and commencing other medicines and vice versa.
-Dietary modifications are recommended in patients taking either selegiline transdermal 9 mg/24 hours or 12 mg/24 hours patches. Tyramine-rich foods and beverages should be avoided beginning on the first day of the 9 mg/24 hours or 12 mg/24 hours patch and for 2 weeks after either a dose reduction to 6 mg/24 hours or following discontinuation of the higher strength patches. Foods and drinks containing little to no tyramine are acceptable; the manufacturer product information should be consulted.

Monitoring:
-Cardiovascular: Blood pressure, tyramine-induced hypertensive crisis
-Nervous system: Exacerbation of dyskinesia (if used concomitantly with levodopa)
-Oncologic: Melanoma
-Psychiatric: Impulse disorders, falling asleep during activities of daily living, somnolence, emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior

Patient advice:
-Tell your healthcare provider about all of the medicines that you take, including prescription and non-prescription medicines.
-This medicine may increase the risk of suicidal thoughts and behavior. Be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report any behavior of concern to your healthcare provider as soon as possible.
-There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges, and the inability to control these urges while taking one or more of the medicines used to treat Parkinson's disease. Be alert for the emergence of these urges. Report any behavior of concern to your healthcare provider as soon as possible.
-Tyramine-rich foods, beverages, and nutritional supplements should be avoided when using the 9 mg/24 hours or 12 mg/24 hours patch.
-Immediately contact your doctor if you experience severe headache, neck stiffness, heart racing or palpitations, or other sudden unusual symptoms.
-Avoid exposing the selegiline transdermal patch application site to external sources of direct heat, such as heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight.
-This medicine may cause drowsiness, impaired judgment, thinking, or motor skills; do not drive a car or operate dangerous machinery until you know how this drug affects you. Contact your doctor if you experience daytime sleepiness or episodes of falling asleep during activities that require participation (e.g., eating).
-Concomitant ingestion of alcohol is not advised.