DRUG INTERACTIONS

 

Selective Serotonin Reuptake Inhibitors: Monitor patients for serotonin syndrome 

 

Sympathomimetic Medications: Monitor patients for hypertension 

Tyramine: Risk of severe hypertension 

 

Substrates of Breast Cancer Resistance Protein (BCRP): 

Potential increase in plasma concentration of BCRP substrate 

BRIEF SUMMARY

 

SAFINAMIDE -(Mar 2017)

 

Indn-        To treat  Parkinsons disease   

 

Comp-       Tablets: 50 mg and 100 mg    Start with 50 mg administered orally once daily at the same time of day;  after two weeks, the dose may be increased to 100 mg once daily, based on individual need and tolerability 

 

ADR-      Most common adverse reactions (incidence on XADAGO 100 mg/day at least 2% greater than placebo) were dyskinesia, fall, nausea, and insomnia 

 

CI- XADAGO is contraindicated in patients with:

 

Concomitant use of the following drugs:

Other monoamine oxidase inhibitors or other drugs that are potent inhibitors 

of monoamine oxidase (e.g., linezolid

 

 

Pat Infm-

Hypertension

Advise patients that treatment with recommended doses of XADAGO may be

 associated with elevations of blood pressure or onset of hypertension. 

 

Tell patients who experience elevation of blood pressure while taking the drug   to contact their healthcare provider.

 

 

=============================================================

 

U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-  7

  

Name of the  Drug-         XADAGO

 

Active Ingredient-           Safinamide                                                                                                                                                                                                             Pharmacological Classification- 

 

To treat  Parkinsons disease                       

                                                                                                                           

Date of Approval-          03-21-2017

 

 (Ref- FDA approved List 2017)                                                                                                                                                                                                                    HIGHLIGHTS OF PRESCRIBING INFORMATION 

These highlights do not include all the information needed to use XADAGO

 safely and effectively. See full prescribing information for XADAGO.

 

XADAGO (safinamide) tablets, for oral use 

Initial U.S. Approval: 2017                                                                                                                                                                                  

                                                                                                                                               INDICATIONS AND USAGE

 

XADAGO is a monoamine oxidase type B (MAO-B) inhibitor indicated as

adjunctive treatment to levodopa/carbidopa in patients with Parkinsons

disease (PD) experiencing on/off episodes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

 

ADVERSE REACTIONS

 

Most common adverse reactions (incidence on XADAGO 100 mg/day at least 2% 

greater than placebo) were dyskinesia, fall, nausea, and insomnia 

 

CONTRAINDICATIONS

 

XADAGO is contraindicated in patients with:

 

Concomitant use of the following drugs:

Other monoamine oxidase inhibitors or other drugs that are potent inhibitors 

of monoamine oxidase (e.g., linezolid) 

 

Opioid drugs (e.g., tramadol, meperidine and related derivatives); 

selective norepinephrine reuptake inhibitors; tri-or tetra-cyclic or triazolopyridine 

antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their 

derivatives; St. John’s wort 

 

 Dextromethorphan 

 

A history of a hypersensitivity to safinamide 

 

Severe hepatic impairment (Child-Pugh C: 10-15) 

 

WARNINGS AND PRECAUTIONS

 

May cause or exacerbate hypertension 

May cause serotonin syndrome when used with MAO inhibitors, antidepressants, 

or opioid drugs 

May cause falling asleep during activities of daily living 

May cause or exacerbate dyskinesia; consider levodopa dose reduction

May cause hallucinations and psychotic behavior 

May cause problems with impulse control/compulsive behaviors 

May cause withdrawal-emergent hyperpyrexia and confusion 

 

INDICATIONS AND USAGE

 

XADAGO is a monoamine oxidase type B (MAO-B) inhibitor indicated as

adjunctive treatment to levodopa/carbidopa in patients with Parkinsons

disease (PD) experiencing on/off episodes

 

Limitations of Use: XADAGO has not been shown to be effective as 

monotherapy for the treatment of PD.

 

DOSAGE AND ADMINISTRATION

 

Start with 50 mg administered orally once daily at the same time of day;

 after two weeks, the dose may be increased to 100 mg once daily, 

based on individual need and tolerability 

 

Hepatic Impairment: Do not exceed 50 mg once daily in patients with 

moderate hepatic impairment; contraindicated in patients with severe 

hepatic impairment 

 

DOSAGE FORMS AND STRENGTHS

Tablets: 50 mg and 100 mg 

 

 PATIENT COUNSELING INFORMATION

 

Advise the patient to read the FDA-approved patient labeling (Patient Information).

 

Hypertension

Advise patients that treatment with recommended doses of XADAGO may be

 associated with elevations of blood pressure or onset of hypertension. 

 

Tell patients who experience elevation of blood pressure while taking

 XADAGO to contact their healthcare provider.

 

Explain the risk of using higher than recommended daily doses of XADAGO,

and provide a brief description of the tyramine associated hypertensive reaction.

 

Advise patients to avoid certain foods (e.g., aged cheese) containing a very

 large amount of tyramine while taking recommended doses of XADAGO

because of the potential for large increases in blood pressure

 

 If patients eat foods very rich in tyramine and do not feel well soon after eating, 

they should contact their healthcare provider

 

Serotonin Syndrome

Tell patients to inform their physician if they are taking, or planning to take, 

any prescription or over-thecounter drugs, especially antidepressants 

and over-the-counter cold medications, because there is a potential for 

interaction with XADAGO. 

 

Because patients should not use meperidine or certain other analgesics with 

XADAGO, they should contact their healthcare provider before taking new 

medications including antidepressants, analgesics, and prescription or 

nonprescription decongestants.

.

Falling Asleep During Activities of Daily Living and Somnolence

Inform patients about the potential for sedating effects associated with XADAGO 

and other dopaminergic medications, including somnolence and particularly 

to the possibility of falling asleep while engaged in activities of daily living. 

 

Because somnolence can be a frequent adverse reaction with potentially serious 

consequences, patients should not operate a motor vehicle or engage in other 

potentially dangerous activities until they have gained sufficient experience with XADAGO.

 

Advise patients that if increased somnolence or new episodes of falling asleep 

during activities of daily living (e.g., watching television, passenger in a car, etc.) 

are experienced at any time during treatment, they should not drive or participate 

in potentially dangerous activities until they have contacted their physician. 

 

Patients should not drive, operate machinery, or work at heights during treatment if 

they have previously experienced somnolence and/or have fallen asleep without

 warning prior to use of XADAGO.

 

Because of possible additive effects, advise patients about the potential for increased 

somnolence when patients are taking other sedating medications, alcohol, or other

 central nervous system depressants (e.g., benzodiazepines, antipsychotics, 

antidepressants) in combination with XADAGO.

 

Dyskinesia

Advise patients taking XADAGO as adjunct to levodopa that there is a possibility 

of dyskinesia or increased dyskinesia .

 

Hallucinations / Psychotic Behavior

Inform patients that hallucinations or other manifestations of psychotic behavior 

can occur when taking XADAGO. Advise patients that, if they have a major 

psychotic disorder, that XADAGO should not ordinarily be used because of the 

risk of exacerbating the psychosis. 

 

Patients with a major psychotic disorder should also be aware that many treatments 

for psychosis may decrease the effectiveness of XADAGO.

 

Impulse Control/Compulsive Behaviors

Advise patients that they may experience intense urges to gamble, increased 

sexual urges, other intense urges, and the inability to control these urges while taking 

XADAGO. 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 XADAGO. 

 

Patients should inform their physician if they experience these urges while taking 

XADAGO .

 

Withdrawal-Emergent Hyperpyrexia and Confusion

Tell patients to contact their healthcare provider if they wish to discontinue 

XADAGO and seek guidance for tapering XADAGO instead of abruptly 

discontinuing XADAGO..

 

Missing Dose

Instruct patients to take XADAGO as prescribed. If a dose is missed, instruct patients

 to take the next dose at the usual time on the following day.

 

Concomitant Medications- Advise patients to inform their physicians if they are taking,

 or plan to take, any prescription or over-the-counter medications because of a 

potential for interactions .

 

Distributed by: US WorldMeds, LLC 4441 Springdale Road Louisville, KY 40241

Reference ID: 4072731 20

Under License from Newron Pharmaceuticals SpA.

 

US WorldMeds, LLC is the exclusive licensee and distributor of XADAGO

 in the United States and Its territories

CLINICAL PHARMACOLOGY

 

1. Mechanism of Action

 The precise mechanism by which XADAGO exerts its effect in Parkinsons disease 

 is unknown. XADAGO is an inhibitor of monoamine oxidase B (MAO-B). Inhibition 

 of MAO-B activity, by blocking the catabolism of dopamine, is thought to result in

  an increase in dopamine levels and a subsequent increase in dopaminergic activity 

  in the brain.

 

2. Pharmacodynamics

 XADAGO inhibits monoamine oxidase B (MAO-B), with more than 1000-fold selectivity

 over MAO-A. In clinical studies, complete inhibition (>90%) of MAO-B was measured at

  doses > 20 mg.

 

Tyramine Challenge Test In an oral tyramine challenge study, XADAGO produced a 

 distinct but relatively small increase in tyramine sensitivity to increase blood pressure. 

 

 The results suggest that XADAGO at a dose of 50 mg or 100 mg is relatively selective 

 for inhibiting MAO-B and can be used without dietary tyramine restriction. 

 

Relative selectivity of XADAGO for inhibiting MAO-B decreases above the highest 

 recommended daily dosage (100 mg) 

 

Cardiac Electrophysiology The effect of XADAGO on the QTc interval was evaluated 

in a randomized placebo and positive controlled double-blind, multiple-dose parallel 

thorough QTc study in 240 healthy subjects. At a dose of 350 mg 

(3.5 times the maximum recommended dosage), XADAGO did not prolong the QTc interval.

 

3. Pharmacokinetics

Pharmacokinetics of safinamide is linear over a range of 50 mg to 300 mg 

(3 times the maximum recommended daily dose). Steady state is reached 

within 5 to 6 days.

 

Absorption 

After single and multiple oral dosing under fasting conditions, Tmax of 

safinamide ranges from 2 to 3 hours. Absolute bioavailability of safinamide is 

95% after oral administration, and first pass metabolism is negligible. 

 A slight delay in Tmax was observed in the fed state relative to the fasted condition,

 but there was no effect on safinamide AUC0. and Cmax 

 

Distribution 

The volume of distribution (Vss) is approximately 165 L, indicating extensive 

extravascular distribution. Safinamide is not highly protein bound

 (unbound fraction is 11 to 12%).

 

Metabolism and Excretion

 In humans, safinamide is almost exclusively eliminated via metabolism 

(~5% of the drug is eliminated unchanged, mainly in urine), through three main

 metabolic pathways. One pathway involves hydrolytic oxidation of the amide 

moiety leading to the primary metabolite esafinamide acid (NW-1153). 

 

Another pathway is oxidative cleavage of the ether bond forming N-debenzylated 

safinamide (NW-1199). Finally, the N-dealkylated acid (NW-1689) is formed 

by oxidative cleavage of the amine bond of either safinamide or the primary

 safinamide acid metabolite (NW-1153). The N-dealkylated acid (NW-1689) 

undergoes further conjugation with glucuronic acid yielding its acyl glucuronide.

 NW-1689 is the main circulating metabolite in human plasma, exceeding the 

exposure of the parent (161% of parent). 

 

NW-1689 AG and NW-1153 account for about 18% and 11% of the parent drug

 exposure, respectively. None of the metabolites has pharmacological activity.

Safinamide is predominantly

 USE IN SPECIFIC POPULATIONS

 

1. Pregnancy

 Pregnancy Category C

There are no adequate and well-controlled studies of XADAGO in pregnant women. 

In animals,developmental toxicity, including teratogenic effects, was observed

when safinamide was administered during pregnancy at clinically relevant doses. 

 

Developmental toxicity was observed at safinamide doses lower than those used 

clinically when safinamide was administered during pregnancy in combination with

 levodopa/carbidopa. XADAGO should be used during pregnancy only if the potential

 benefit justifies the potential risk to the fetus.

 

2.Nursing Mothers

 Skin discoloration, presumed to be caused by hyperbilirubinemia resulting from 

 hepatobiliary toxicity, was observed in rat pups indirectly exposed to safinamide through

 the milk during the lactation period. 

 

It is not known whether this drug is present in human milk. Because many drugs are 

excreted in human milk and because of the potential for serious adverse reactions 

in nursing infants from safinamide, a decision should be made whether to discontinue 

nursing or to discontinue the drug, taking into account the importance of the drug 

to the mother.

 

3.Pediatric Use

 The safety and effectiveness of XADAGO in pediatric patients have not been 

 established. No juvenile toxicity studies have been performed in animals.

 

4.Geriatric Use

 Of the 1516 subjects exposed to XADAGO in clinical studies, 38% were 65 and over, 

 while 4% were 75 and over. No overall differences in safety or effectiveness were 

 observed between these patients and younger patients, and other reported clinical

 experience has not identified differences in responses between the elderly and 

 younger patients, but greater sensitivity of some older individuals cannot be ruled out.

 

5.Hepatic Impairment

 XADAGO plasma concentrations are increased in patients with hepatic impairment 

 In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum 

 recommended dosage of XADAGO is 50 mg once daily 

 

 XADAGO has not been studied in patients with severe hepatic impairment 

(Child-Pugh C: 10-15), and is contraindicated in these patients. 

 If patients progress from moderate to severe hepatic impairment, treatment with

 XADAGO should be stopped.

 

 OVERDOSAGE

There is no human experience with XADAGO overdose.

There is no known antidote to XADAGO nor any specific treatment for XADAGO

 overdose. If an important overdose occurs, XADAGO treatment should be 

 discontinued and supportive treatment should be administered as clinically 

 indicated. 

 

In cases of overdose with XADAGO, dietary tyramine restriction should be observed 

for several weeks