| CLINICAL PHARMACOLOGY
Mechanism of Action: Antiviral
The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.
Mechanism of Action: Parkinson's Disease
Parkinson's disease or Creutzfeldt-Jakob disease (unlabeled use): 100 mg twice daily as sole therapy; may increase to 400 mg/day if needed with close monitoring; initial dose: 100 mg/day if with other serious illness or with high doses of other anti-Parkinson drugs
Influenza A viral infection: 100 mg twice daily; initiate within 24-48 hours after onset of symptoms; discontinue as soon as possible based on clinical response (generally within 3-5 days or within 24-48 hours after symptoms disappear). Influenza A prophylaxis: 100 mg twice daily
Note: Continue treatment throughout the peak influenza activity in the community or throughout the entire influenza season in patients who cannot be vaccinated. Development of immunity following vaccination takes ~2 weeks; amantadine therapy should be considered for high-risk patients from the time of vaccination until immunity has developed
Hemodialysis: Administer 200 mg every 7 days
Benztropine mesylate possesses both anticholinergic and antihist-aminic effects, although only the former have been established as therapeutically significant in the management of parkinsonism.
In the isolated guinea pig ileum, the anticholinergic activity of this drug is about equal to that of atropine; however, when adminis-tered orally to unanesthetized cats, it is only about half as active as atropine.
In laboratory animals, its antihistaminic activity and duration of action approach those of pyrilamine maleate.
Acute dystonia: Adults: I.M., I.V.: 1-2 mg
Adults: 0.5-6 mg/day in 1-2 divided doses; if one dose is greater, administer at bedtime; titrate dose in 0.5 mg increments at 5- to 6-day intervals
Elderly: Initial: 0.5 mg once or twice daily; increase by 0.5 mg as needed at 5-6 days; maximum: 4 mg/day
| Dopamine agonist.
Parlodel® (bromocriptine mesylate) is a dopamine receptor agonist, which activates post-synaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function. Clinically, Parlodel significantly reduces plasma levels of prolactin in patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic hormones from the anterior pituitary. Experiments have demonstrated that bromocriptine induces longlasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions in the substantia nigra. These actions, characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine receptors.
Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients.
In about 75% of cases of amenorrhea and galactorrhea, Parlodel therapy suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles.
Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on average is 6-8 weeks. However, some patients respond within a few days, and others may take up to 8 months.
Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8-12 weeks. Some patients may fail to respond even after 12 months of therapy.
In many acromegalic patients, Parlodel produces a prompt and sustained reduction in circulating levels of serum growth hormone.
Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson's disease, a clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are known to be numerically diminished in this patient population.
Neuroleptic malignant syndrome: 2.5-5 mg 3 times/day
Acromegaly: Initial: 1.25-2.5 mg increasing as necessary every 3-7 days; usual dose: 20-30 mg/day
Prolactin-secreting adenomas: Initial: 1.25-2.5 mg/day; may be increased as tolerated every 2-7 days until optimal response (range: 2.5-15 mg/day)
| CLINICAL PHARMACOLOGY
Mechanism of Action
Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).
In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells, and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.
The mechanism of action of entacapone is believed to be through its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's Disease. The higher levodopa levels also lead to increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa.
| Pergolide mesylate is a potent dopamine receptor agonist. Pergolide is 10 to 1,000 times more potent than bromocriptine on a milligram per milligram basis in various in vitro and in vivo test systems. Pergolide mesylate inhibits the secretion of prolactin in humans; it causes a transient rise in serum concentrations of growth hormone and a decrease in serum concentrations of luteinizing hormone. In Parkinsons disease, pergolide mesylate is believed to exert its therapeutic effect by directly stimulating postsynaptic dopamine receptors in the nigrostriatal system.
Adults: Parkinson's disease: Start with 0.05 mg/day for 2 days, then increase dosage by 0.1 or 0.15 mg/day every 3 days over next 12 days, increase dose by 0.25 mg/day every 3 days until optimal therapeutic dose is achieved, up to 5 mg/day maximum; usual dosage range: 2-3 mg/day in 3 divided doses
| Mechanism of Action
Pramipexole is a nonergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.
Restless Legs Syndrome (RLS)
| Mechanism of Action:
AZILECT functions as a selective, irreversible MAO-B inhibitor indicated for the treatment of idiopathic Parkinson's disease. The results of a clinical trial designed to examine the effects of Azilect on blood pressure when it is administered with increasing doses of tyramine indicates the functional selectivity can be incomplete when healthy subjects ingest large amounts of tyramine while receiving recommended doses of AZILECT. The selectivity for inhibiting MAO-B diminishes in a dose-related manner.
INDICATIONS AND USAGE:
USE IN SPECIFIC POPULATIONS
DOSAGE AND ADMINISTRATION:
Patients with mild hepatic impairment: AZILECT 0.5 mg once daily should not be exceeded. AZILECT should not be used in patients with moderate or severe hepatic impairment.
AZILECT has not been studied in patients with severe renal impairment.
Patients taking ciprofloxacin or other CYP1A2 inhibitors: AZILECT 0.5 mg once daily should not be exceeded.
DOSAGE FORMS AND STRENGTHS:
WARNINGS AND PRECAUTIONS
To report SUSPECTED ADVERSE REACTIONS, contact TEVA at 1-800-221-4026 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
| Mechanism of Action
REQUIP is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 and D3 dopamine receptor subtypes, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.
Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D1, 5-HT1, 5-HT2, benzodiazepine, GABA, muscarinic, alpha1-, alpha2-, and beta-adrenoreceptors.
Parkinson's Disease: The precise mechanism of action of REQUIP as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of postsynaptic dopamine D2-type receptors within the caudate-putamen in the brain. This conclusion is supported by studies that show that ropinirole improves motor function in various animal models of Parkinson's disease. In particular, ropinirole attenuates the motor deficits induced by lesioning the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates. The relevance of D3 receptor binding in Parkinson's disease is unknown.
Restless Legs Syndrome (RLS): The precise mechanism of action of REQUIP as a treatment for Restless Legs Syndrome (also known as Ekbom Syndrome) is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS.
Week 1: 0.25 mg 3 times/day; total daily dose: 0.75 mg
Week 2: 0.5 mg 3 times/day; total daily dose: 1.5 mg
Week 3: 0.75 mg 3 times/day; total daily dose: 2.25 mg
Week 4: 1 mg 3 times/day; total daily dose: 3 mg
After week 4, if necessary, daily dosage may be increased by 1.5 mg per day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly to a total of 24 mg/day
Removal by hemodialysis is unlikely.
| INDICATIONS AND USAGE
Neupro is a dopamine agonist indicated for the treatment of:
-Signs and symptoms of Parkinson's disease
-Moderate-to-severe primary Restless Legs Syndrome
DOSAGE AND ADMINISTRATION
Parkinson's disease: Initially, 2 mg/24 hours for early-stage disease or 4 mg/24 hours for advanced-stage disease. The dose may be increased as needed by 2 mg/24 hours at weekly intervals, up to 6 mg /24 hours for early-stage disease and up to 8 mg/24 hours for advanced-stage disease.
Restless Legs Syndrome: Initially, 1 mg/24 hours, increased as needed by 1 mg/24 hours at weekly intervals, up to 3 mg/24 hours.
To discontinue treatment, reduce the dose gradually until complete withdrawal of Neupro.
DOSAGE FORMS AND STRENGTHS
| Drug UPDATES: XADAGO ® (safinamide) tablets
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Initial U.S. Approval: 2017
Mechanism of Action:
INDICATIONS AND USAGE:
Limitations of Use: XADAGO has not been shown to be effective as monotherapy for the treatment of PD.
DOSAGE AND ADMINISTRATION:
Daily dosages of XADAGO above 100 mg have not been shown to provide additional benefit, and higher dosages increase the risk for adverse reactions. XADAGO has been shown to be effective only in combination with levodopa/carbidopa [see INDICATIONS AND USAGE (1)].
If a dose is missed, the next dose should be taken at the same time the next day.
XADAGO 100 mg should be tapered by decreasing the dose to 50 mg for one week before stopping [see WARNINGS AND PRECAUTIONS (5.7)].
2.2 Dosing in Patients with Hepatic Impairment
| CLINICAL PHARMACOLOGY
The mechanisms accounting for selegiline's beneficial adjunctive action in the treatment of Parkinson's disease are not fully understood. Inhibition of monoamine oxidase, type B, activity is generally considered to be of primary importance; in addition, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity.
Selegiline is best known as an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. Selegiline inhibits MAO by acting as a 'suicide' substrate for the enzyme; that is, it is converted by MAO to an active moiety which combines irreversibly with the active site and/or the enzyme's essential FAD cofactor. Because selegiline has greater affinity for type B rather than for type A active sites, it can serve as a selective inhibitor of MAO type B if it is administered at the recommended dose.
Elderly: Parkinson's disease: Initial: 5 mg in the morning, may increase to a total of 10 mg/day
| Mechanism of Action
Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease.
Immediate release tablet:
Initial: Carbidopa 25 mg/levodopa 100 mg 3 times/day
Dosage adjustment: Alternate tablet strengths may be substituted according to individual carbidopa/levodopa requirements. Increase by 1 tablet every other day as necessary, except when using the carbidopa 25 mg/levodopa 250 mg tablets where increases should be made using 1 /2-1 tablet every 1-2 days. Use of more than 1 dosage strength or dosing 4 times/day may be required (maximum: 8 tablets of any strength/day or 200 mg of carbidopa and 2000 mg of levodopa)
Sustained release tablet:
Dosage adjustment: May adjust every 3 days; intervals should be between 4-8 hours during the waking day (maximum: 8 tablets/day)
Restless leg syndrome (unlabeled use): Carbidopa 25 mg/levodopa 100 mg given 30-60 minutes before bedtime; may repeat dose once
Elderly: Initial: Carbidopa 25 mg/levodopa 100 mg twice daily, increase as necessary
Tablet, immediate release, orally-disintegrating (Parcopa™):
Tablet, sustained release (Sinemet® CR):
U.S. Approval: 2015 [Initial U.S. Approval: 1975 ]
Mechanism of Action:
INDICATIONS AND USAGE: DUOPA is a combination of carbidopa (an aromatic amino acid decarboxylation inhibitor) and levodopa (an aromatic amino acid) indicated for the treatment of motor fluctuations in patients with advanced Parkinson’s disease
HOW SUPPLIED: Enteral suspension: 4.63 mg carbidopa and 20 mg levodopa per mL in a single-use cassette. Each cassette contains approximately 100 mL of suspension.
| Stalevo® (carbidopa, levodopa and entacapone) is indicated to treat patients with idiopathic Parkinson's disease.
DOSAGE AND ADMINISTRATION
Generally speaking, Stalevo® (carbidopa, levodopa and entacapone) should be used as a substitute for patients already stabilized on equivalent doses of carbidopa-levodopa and entacapone. However, some patients who have been stabilized on a given dose of carbidopa-levodopa may be treated with Stalevo® if a decision has been made to add entacapone (see below).
The optimum daily dosage of Stalevo® must be determined by careful titration in each patient. Stalevo® tablets are available in six strengths, each in a 1:4 ratio of carbidopa to levodopa and combined with 200 mg of entacapone in a standard release formulation (Stalevo® 50 containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone; Stalevo® 75, containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone; Stalevo® 100 containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone; Stalevo® 125, containing 31.25 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone; Stalevo® 150 containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone; and Stalevo® 200 containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of entacapone).
Therapy should be individualized and adjusted according to the desired therapeutic response.
Studies show that peripheral dopa decarboxylase is saturated by carbidopa at approximately 70 mg to 100 mg a day. Patients receiving less than this amount of carbidopa are more likely to experience nausea and vomiting.
Clinical experience with daily doses above 1600 mg of entacapone is limited. It is recommended that no more than one Stalevo® tablet be taken at each dosing administration.
Thus the maximum recommended daily dose of Stalevo® 50, Stalevo® 75, Stalevo® 100, Stalevo® 125 and Stalevo® 150, defined by the maximum daily dose of entacapone, is eight tablets per day. Because there is limited experience with total daily doses of carbidopa greater than 300mg, the maximum recommended daily dose of Stalevo® 200 is six tablets per day.
How to transfer patients taking carbidopa-levodopa preparations and Comtan® (entacapone) tablets to Stalevo® (carbidopa, levodopa and entacapone) tablets
Patients who are currently treated with Comtan 200 mg tablet with each dose of standard-release carbidopa-levodopa, can be directly switched to the corresponding strength of Stalevo® containing the same amounts of levodopa and carbidopa. For example, patients receiving one tablet of standard-release carbidopa-levodopa 25/100 mg and one tablet of Comtan 200 mg at each administration can be switched to a single Stalevo® 100 tablet (containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone).
How to transfer patients not currently treated with Comtan® (entacapone) tablets from carbidopa-levodopa to Stalevo® (carbidopa, levodopa and entacapone) tablets
In patients who take a total daily levodopa dose up to 600 mg, and who do not have dyskinesias, an attempt can be made to transfer to the corresponding daily dose of Stalevo® . Even in these patients, a reduction of carbidopa-levodopa or entacapone may be necessary however, the provider is reminded that this may not be possible with Stalevo® . Since entacapone prolongs and enhances the effects of levodopa, therapy should be individualized and adjusted if necessary according to the desired therapeutic response.
Maintenance of Stalevo® Treatment
When less levodopa is required, the total daily dosage of carbidopa-levodopa should be reduced by either decreasing the strength of Stalevo® at each administration or by decreasing the frequency of administration by extending the time between doses.
When more levodopa is required, the next higher strength of Stalevo® should be taken and/or the frequency of doses should be increased, up to a maximum of 8 times daily of Stalevo® 50, Stalevo® 75, Stalevo® 100, Stalevo® 125 and Stalevo® 150, and maximum of 6 times daily of Stalevo® 200.
Addition of Other Antiparkinsonian Medications
Interruption of Therapy
| Mechanism of Action
Tolcapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).
In mammals, COMT is distributed throughout various organs. The highest activities are in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.
The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson’s disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. Tolcapone enters the CNS to a minimal extent, but has been shown to inhibit central COMT activity in animals.
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