Myotonine

Myotonine may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

UK matches:

• Myotonine 10 mg (Bethanechol Chloride) (SPC)
• Myotonine 25 mg (Bethanechol Chloride) (SPC)

Ingredient matches for Myotonine

Bethanechol

Bethanechol Chloride is reported as an ingredient of Myotonine in the following countries:

• United Kingdom

International Drug Name Search

Glossary

SPC	Summary of Product Characteristics (UK)

Click for further information on drug naming conventions and International Nonproprietary Names.

Levaquin

Generic Name: levofloxacin

Dosage Form: tablets, oral solution, injection
FULL PRESCRIBING INFORMATION

WARNING:

Fluoroquinolones, including Levaquin®, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants [See Warnings and Precautions (5.1)].

 Fluoroquinolones, including Levaquin®, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid Levaquin® in patients with a known history of myasthenia gravis [See Warnings and Precautions (5.2)].

Indications and Usage for Levaquin

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Levaquin® and other antibacterial drugs, Levaquin® should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Levaquin® Tablets/Injection and Oral Solution are indicated for the treatment of adults (≥18 years of age) with mild, moderate, and severe infections caused by susceptible strains of the designated microorganisms in the conditions listed in this section. Levaquin® Injection is indicated when intravenous administration offers a route of administration advantageous to the patient (e.g., patient cannot tolerate an oral dosage form).

Culture and susceptibility testing

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing the infection and to determine their susceptibility to levofloxacin [see Clinical Pharmacology (12.4)]. Therapy with Levaquin® may be initiated before results of these tests are known; once results become available, appropriate therapy should be selected.

As with other drugs in this class, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with Levaquin®. Culture and susceptibility testing performed periodically during therapy will provide information about the continued susceptibility of the pathogens to the antimicrobial agent and also the possible emergence of bacterial resistance.

Nosocomial Pneumonia

Levaquin® is indicated for the treatment of nosocomial pneumonia due to methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae. Adjunctive therapy should be used as clinically indicated. Where Pseudomonas aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is recommended [see Clinical Studies (14.1)].

Community-Acquired Pneumonia: 7–14 day Treatment Regimen

Levaquin® is indicated for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant Streptococcus pneumoniae [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Dosage and Administration (2.1) and Clinical Studies (14.2)].

MDRSP isolates are strains resistant to two or more of the following antibacterials: penicillin (MIC ≥2 mcg/mL), 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Community-Acquired Pneumonia: 5-day Treatment Regimen

Levaquin® is indicated for the treatment of community-acquired pneumonia due to Streptococcus pneumoniae (excluding multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Dosage and Administration (2.1) and Clinical Studies (14.3)].

Acute Bacterial Sinusitis: 5-day and 10–14 day Treatment Regimens

Levaquin® is indicated for the treatment of acute bacterial sinusitis due to Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis [see Clinical Studies (14.4)].

Acute Bacterial Exacerbation of Chronic Bronchitis

Levaquin® is indicated for the treatment of acute bacterial exacerbation of chronic bronchitis due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.

Complicated Skin and Skin Structure Infections

Levaquin® is indicated for the treatment of complicated skin and skin structure infections due to methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis [see Clinical Studies (14.5)].

Uncomplicated Skin and Skin Structure Infections

Levaquin® is indicated for the treatment of uncomplicated skin and skin structure infections (mild to moderate) including abscesses, cellulitis, furuncles, impetigo, pyoderma, wound infections, due to methicillin-susceptible Staphylococcus aureus, or Streptococcus pyogenes.

Chronic Bacterial Prostatitis

Levaquin® is indicated for the treatment of chronic bacterial prostatitis due to Escherichia coli, Enterococcus faecalis, or methicillin-susceptible Staphylococcus epidermidis [see Clinical Studies (14.6)].

Complicated Urinary Tract Infections: 5-day Treatment Regimen

Levaquin® is indicated for the treatment of complicated urinary tract infections due to Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis [see Clinical Studies (14.7)].

Complicated Urinary Tract Infections: 10-day Treatment Regimen

Levaquin® is indicated for the treatment of complicated urinary tract infections (mild to moderate) due to Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa [see Clinical Studies (14.8)].

Acute Pyelonephritis: 5 or 10-day Treatment Regimen

Levaquin® is indicated for the treatment of acute pyelonephritis caused by Escherichia coli, including cases with concurrent bacteremia [see Clinical Studies (14.7, 14.8)].

Uncomplicated Urinary Tract Infections

Levaquin® is indicated for the treatment of uncomplicated urinary tract infections (mild to moderate) due to Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophyticus.

Inhalational Anthrax (Post-Exposure)

Levaquin® is indicated for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. The effectiveness of Levaquin® is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. Levaquin® has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of Levaquin® in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied. Prolonged Levaquin® therapy should only be used when the benefit outweighs the risk [see Dosage and Administration (2.1, 2.2) and Clinical Studies (14.9)].

Levaquin Dosage and Administration

Dosage in Adult Patients with Normal Renal Function

The usual dose of Levaquin® Tablets or Oral Solution is 250 mg, 500 mg, or 750 mg administered orally every 24 hours, as indicated by infection and described in Table 1. The usual dose of Levaquin® Injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours, as indicated by infection and described in Table 1.

These recommendations apply to patients with creatinine clearance ≥ 50 mL/min. For patients with creatinine clearance <50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration (2.3)].

Table 1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance ≥ 50 mL/min)

Type of Infection*	Dosed Every 24 hours	Duration (days)†
* Due to the designated pathogens [see Indications and Usage (1)]. † Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. ‡ Due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Indications and Usage (1.2)]. § Due to Streptococcus pneumoniae (excluding multi-drug-resistant strains [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and Usage (1.3)]. ¶ This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and AP due to E. coli, including cases with concurrent bacteremia. # This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; and for AP due to E. coli. Þ Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9)]. ß The safety of Levaquin® in adults for durations of therapy beyond 28 days or in pediatric patients for durations beyond 14 days has not been studied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.4), and Clinical Studies (14.9)]. Prolonged Levaquin® therapy should only be used when the benefit outweighs the risk.
Nosocomial Pneumonia	750 mg	7–14
Community Acquired Pneumonia‡	500 mg	7–14
Community Acquired Pneumonia§	750 mg	5
Acute Bacterial Sinusitis	750 mg	5
	500 mg	10–14
Acute Bacterial Exacerbation of Chronic Bronchitis	500 mg	7
Complicated Skin and Skin Structure Infections (SSSI)	750 mg	7–14
Uncomplicated SSSI	500 mg	7–10
Chronic Bacterial Prostatitis	500 mg	28
Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)¶	750 mg	5
Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)#	250 mg	10
Uncomplicated Urinary Tract Infection	250 mg	3
Inhalational Anthrax (Post-Exposure), adult and pediatric patients > 50 kg and ≥ 6 months of ageÞ,ß	500 mg	60ß
Pediatric patients < 50 kg and ≥ 6 months of ageÞ,ß	see Table 2 below (2.2)	60ß

Dosage in Pediatric Patients

The dosage in pediatric patients ≥ 6 months of age is described below in Table 2.

Table 2: Dosage in Pediatric Patients ≥ 6 months of age

Type of Infection*	Dose	Freq. Once every	Duration†
* Due to Bacillus anthracis [see Indications and Usage (1.13)] † Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician. ‡ Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on a surrogate endpoint. Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9)] § The safety of Levaquin® in pediatric patients for durations of therapy beyond 14 days has not been studied. An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.4), and Clinical Studies (14.9)]. Prolonged Levaquin® therapy should only be used when the benefit outweighs the risk.
Inhalational Anthrax (post-exposure)‡,§
Pediatric patients > 50 kg and ≥ 6 months of age	500 mg	24 hr	60 days§
Pediatric patients < 50 kg and ≥ 6 months of age	8 mg/kg (not to exceed 250 mg per dose)	12 hr	60 days§

Dosage Adjustment in Adults with Renal Impairment

Administer Levaquin® with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced.

No adjustment is necessary for patients with a creatinine clearance ≥ 50 mL/min.

In patients with impaired renal function (creatinine clearance <50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [see Use in Specific Populations (8.6)].

Table 3 shows how to adjust dose based on creatinine clearance.

Table 3: Dosage Adjustment in Adult Patients with Renal Impairment (creatinine clearance <50 mL/min)

Dosage in Normal Renal Function Every 24 hours	Creatinine Clearance 20 to 49 mL/min	Creatinine Clearance 10 to 19 mL/min	Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD)
750 mg	750 mg every 48 hours	750 mg initial dose, then 500 mg every 48 hours	750 mg initial dose, then 500 mg every 48 hours
500 mg	500 mg initial dose, then 250 mg every 24 hours	500 mg initial dose, then 250 mg every 48 hours	500 mg initial dose, then 250 mg every 48 hours
250 mg	No dosage adjustment required	250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required	No information on dosing adjustment is available

Drug Interaction With Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

Levaquin® Tablets and Oral Solution

Levaquin® Tablets and Oral Solution should be administered at least two hours before or two hours after antacids containing magnesium, aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine chewable/buffered tablets or the pediatric powder for oral solution [see Drug Interactions (7.1) and Patient Counseling Information (17.2)].

Levaquin® Injection

Levaquin® Injection should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration (2.6)].

Administration Instructions

Food and Levaquin® Tablets and Oral Solution

Levaquin® Tablets can be administered without regard to food. It is recommended that Levaquin® Oral Solution be taken 1 hour before or 2 hours after eating.

Levaquin® Injection

Caution: Rapid or bolus intravenous infusion of Levaquin® has been associated with hypotension and must be avoided. Levaquin® Injection should be infused intravenously slowly over a period of not less than 60 or 90 minutes, depending on the dosage. Levaquin® Injection should be administered only by intravenous infusion. It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

Hydration for Patients Receiving Levaquin® Tablets, Oral Solution, and Injection

Adequate hydration of patients receiving oral or intravenous Levaquin® should be maintained to prevent the formation of highly concentrated urine. Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions (6.1) and Patient Counseling Information (17.2)].

Preparation of Intravenous Product

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Because only limited data are available on the compatibility of Levaquin® Injection with other intravenous substances, additives or other medications should not be added to Levaquin® Injection Premix in Single-Use Flexible Containers and Levaquin® Injection in Single-Use Vials, or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of Levaquin® Injection with an infusion solution compatible with Levaquin® Injection and with any other drug(s) administered via this common line.

Levaquin® Injection in Single-Use Vials

Single-use vials require dilution prior to administration.

Levaquin® Injection is supplied in single-use vials containing a concentrated levofloxacin solution with the equivalent of 500 mg (20 mL vial) and 750 mg (30 mL vial) of levofloxacin in Water for Injection, USP. The 20 mL and 30 mL vials each contain 25 mg of levofloxacin/mL. These Levaquin® Injection single-use vials must be further diluted with an appropriate solution prior to intravenous administration [see Table 4]. The concentration of the resulting diluted solution should be 5 mg/mL prior to administration.

Compatible Intravenous Solutions: Any of the following intravenous solutions may be used to prepare a 5 mg/mL levofloxacin solution with the approximate pH values:

Table 4: Compatible Intravenous Solutions

Intravenous Fluids	Final pH of Levaquin® Solution
0.9% Sodium Chloride Injection, USP	4.71
5% Dextrose Injection, USP	4.58
5% Dextrose/0.9% NaCl Injection	4.62
5% Dextrose in Lactated Ringers	4.92
Plasma-Lyte® 56/5% Dextrose Injection	5.03
5% Dextrose, 0.45% Sodium Chloride, and 0.15% Potassium Chloride Injection	4.61
Sodium Lactate Injection (M/6)	5.54

Since no preservative or bacteriostatic agent is present in this product, aseptic technique must be used in preparation of the final intravenous solution. Since the vials are for single-use only, any unused portion remaining in the vial should be discarded. When used to prepare two 250 mg doses from the 20 mL vial containing 500 mg of levofloxacin, the full content of the vial should be withdrawn at once using a single-entry procedure, and a second dose should be prepared and stored for subsequent use [see Stability of Levaquin® Injection Following Dilution].

Prepare the desired dosage of levofloxacin according to Table 5:

Table 5: Preparation of Levaquin® Intravenous Solution

Desired Dosage Strength	From Appropriate Vial, Withdraw Volume	Volume of Diluent	Infusion Time
250 mg	10 mL (20 mL Vial)	40 mL	60 min
500 mg	20 mL (20 mL Vial)	80 mL	60 min
750 mg	30 mL (30 mL Vial)	120 mL	90 min

For example, to prepare a 500 mg dose using the 20 mL vial (25 mg/mL), withdraw 20 mL and dilute with a compatible intravenous solution to a total volume of 100 mL.

This intravenous drug product should be inspected visually for particulate matter prior to administration. Samples containing visible particles should be discarded.

Stability of Levaquin® Injection Following Dilution: Levaquin® Injection, when diluted in a compatible intravenous fluid to a concentration of 5 mg/mL, is stable for 72 hours when stored at or below 25°C (77°F) and for 14 days when stored under refrigeration at 5°C (41°F) in plastic intravenous containers. Solutions that are diluted in a compatible intravenous solution and frozen in glass bottles or plastic intravenous containers are stable for 6 months when stored at - 20°C (- 4°F). Thaw frozen solutions at room temperature 25°C (77°F) or in a refrigerator 8°C (46°F). Do not force thaw by microwave irradiation or water bath immersion. Do not refreeze after initial thawing.

Levaquin® Injection Premix in Single-Use Flexible Containers (5 mg/mL)

Levaquin® Injection is also supplied in flexible containers within a foil overwrap. These contain a premixed, ready to use levofloxacin solution in 5% dextrose (D5W) for single-use. The 100 mL premixed flexible containers contain either 250 mg/50 mL or 500 mg/100 mL of levofloxacin solution. The 150 mL flexible container contains 750 mg/150 mL of levofloxacin solution. The concentration of each container is 5 mg/mL. No further dilution of these preparations is necessary. Because the premix flexible containers are for single-use only, any unused portion should be discarded.

Instructions for the Use of Levaquin® Injection Premix in Flexible Containers:

1. Tear outer wrap at the notch and remove solution container.


2. Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as the sterility may be compromised.


3. Do not use if the solution is cloudy or a precipitate is present.


4. Use sterile equipment.


5. WARNING: Do not use flexible containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Preparation for Administration:

1. Close flow control clamp of administration set.


2. Remove cover from port at bottom of container.


3. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.


4. Suspend container from hanger.


5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levaquin® Injection Premix in Flexible Containers.


6. Open flow control clamp to expel air from set. Close clamp.


7. Regulate rate of administration with flow control clamp.

Dosage Forms and Strengths

TABLETS, Film-coated, capsule-shaped

• 250 mg terra cotta pink tablets, imprinted with "250" on one side and "Levaquin" on the other


• 500 mg peach tablets, imprinted with "500" on one side and "Levaquin" on the other


• 750 mg white tablets, imprinted with "750" on one side and "Levaquin" on the other

ORAL SOLUTION, 25mg/mL, clear yellow to clear greenish-yellow color

INJECTION, Single-Use Vials of concentrated solution for dilution for intravenous infusion, clear yellow to clear greenish-yellow in appearance

• 20 mL vial of 25 mg/mL levofloxacin solution, equivalent to 500 mg of levofloxacin


• 30 mL vial of 25 mg/mL levofloxacin solution, equivalent to 750 mg of levofloxacin

INJECTION (5 mg/mL in 5% Dextrose) Premix in Single-Use Flexible Containers, for intravenous infusion

• 100 mL container, fill volume 50 mL (equivalent to 250 mg levofloxacin)


• 100 mL container, fill volume 100 mL (equivalent to 500 mg levofloxacin)


• 150 mL container, fill volume 150 mL (equivalent to 750 mg levofloxacin)

Contraindications

Levaquin® is contraindicated in persons with known hypersensitivity to levofloxacin, or other quinolone antibacterials [see Warnings and Precautions (5.3)].

Warnings and Precautions

Tendinopathy and Tendon Rupture

Fluoroquinolones, including Levaquin®, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in those taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have been reported in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Levaquin® should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug. [see Adverse Reactions (6.3); Patient Counseling Information (17.3)].

Exacerbation of Myasthenia Gravis

 Fluoroquinolones, including Levaquin®, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid Levaquin® in patients with a known history of myasthenia gravis [see Adverse Reactions (6.3); Patient Counseling Information (17.3)].

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including Levaquin®. These reactions often occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions. Levaquin® should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated [see Adverse Reactions (6); Patient Counseling Information (17.3)].

Other Serious and Sometimes Fatal Reactions

Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with fluoroquinolones, including Levaquin®. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome);


• vasculitis; arthralgia; myalgia; serum sickness;


• allergic pneumonitis;


• interstitial nephritis; acute renal insufficiency or failure;


• hepatitis; jaundice; acute hepatic necrosis or failure;


• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

The drug should be discontinued immediately at the first appearance of skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Adverse Reactions (6); Patient Counseling Information (17.3)].

Hepatotoxicity

Post-marketing reports of severe hepatotoxicity (including acute hepatitis and fatal events) have been received for patients treated with Levaquin®. No evidence of serious drug-associated hepatotoxicity was detected in clinical trials of over 7,000 patients. Severe hepatotoxicity generally occurred within 14 days of initiation of therapy and most cases occurred within 6 days. Most cases of severe hepatotoxicity were not associated with hypersensitivity [see Warnings and Precautions (5.4)]. The majority of fatal hepatotoxicity reports occurred in patients 65 years of age or older and most were not associated with hypersensitivity. Levaquin® should be discontinued immediately if the patient develops signs and symptoms of hepatitis [see Adverse Reactions (6); Patient Counseling Information (17.3)].

Central Nervous System Effects

 Convulsions, toxic psychoses, increased intracranial pressure (including pseudotumor cerebri) have been reported in patients receiving fluoroquinolones, including Levaquin®. Fluoroquinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving Levaquin®, the drug should be discontinued and appropriate measures instituted. As with other fluoroquinolones, Levaquin® should be used with caution in patients with a known or suspected central nervous system (CNS) disorder that may predispose them to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose them to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction.) [see Adverse Reactions (6); Drug Interactions (7.4, 7.5); Patient Counseling Information (17.3)].

Clostridium difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Levaquin®, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated [see Adverse Reactions (6.2), Patient Counseling Information (17.3)].

Peripheral Neuropathy

Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including Levaquin®. Levaquin® should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness or other alterations of sensation including light touch, pain, temperature, position sense, and vibratory sensation in order to prevent the development of an irreversible condition [see Adverse Reactions (6), Patient Counseling Information (17.3)].

Prolongation of the QT Interval

Some fluoroquinolones, including Levaquin®, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including Levaquin®. Levaquin® should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Adverse Reactions (6.3), Use in Specific Populations (8.5), and Patient Counseling Information (17.3)].

Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

Levaquin® is indicated in pediatric patients (≥6 months of age) only for the prevention of inhalational anthrax (post-exposure) [see Indications and Usage (1.13)]. An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormality) compared to controls has been observed in pediatric patients receiving Levaquin®[see Use in Specific Populations (8.4)].

In immature rats and dogs, the oral and intravenous administration of levofloxacin resulted in increased osteochondrosis. Histopathological examination of the weight-bearing joints of immature dogs dosed with levofloxacin revealed persistent lesions of the cartilage. Other fluoroquinolones also produce similar erosions in the weight-bearing joints and other signs of arthropathy in immature animals of various species [see Animal Toxicology and/or Pharmacology (13.2)].

Blood Glucose Disturbances

As with other fluoroquinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported with Levaquin®, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (e.g., glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. If a hypoglycemic reaction occurs in a patient being treated with Levaquin®, Levaquin® should be discontinued and appropriate therapy should be initiated immediately [see Adverse Reactions (6.2); Drug Interactions (7.3); Patient Counseling Information (17.4)].

Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of fluoroquinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if photosensitivity/phototoxicity occurs [see Adverse Reactions (6.3); Patient Counseling Information (17.3)].

Development of Drug Resistant Bacteria

Prescribing Levaquin® in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Patient Counseling Information (17.1)].

Adverse Reactions

Serious and Otherwise Important Adverse Reactions

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

• Tendon Effects [see Warnings and Precautions (5.1)]


• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.2)]


• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]


• Other Serious and Sometimes Fatal Reactions [see Warnings and Precautions (5.4)]


• Hepatotoxicity [see Warnings and Precautions (5.5)]


• Central Nervous System Effects [see Warnings and Precautions (5.6)]


• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.7)]


• Peripheral Neuropathy [see Warnings and Precautions (5.8)]


• Prolongation of the QT Interval [see Warnings and Precautions (5.9)]


• Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions (5.10)]


• Blood Glucose Disturbances [see Warnings and Precautions (5.11)]


• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.12)]


• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.13)]

Hypotension has been associated with rapid or bolus intravenous infusion of Levaquin®. Levaquin® should be infused slowly over 60 to 90 minutes, depending on dosage [see Dosage and Administration (2.5)].

Crystalluria and cylindruria have been reported with quinolones, including Levaquin®. Therefore, adequate hydration of patients receiving Levaquin® should be maintained to prevent the formation of a highly concentrated urine [see Dosage and Administration (2.5)].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Levaquin® in 7537 patients in 29 pooled Phase 3 clinical trials. The population studied had a mean age of 50 years (approximately 74% of the population was < 65 years of age), 50% were male, 71% were Caucasian, 19% were Black. Patients were treated with Levaquin® for a wide variety of infectious diseases [see Indications and Usage (1)]. Patients received Levaquin® doses of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. Treatment duration was usually 3–14 days, and the mean number of days on therapy was 10 days.

The overall incidence, type and distribution of adverse reactions was similar in patients receiving Levaquin® doses of 750 mg once daily, 250 mg once daily, and 500 mg once or twice daily. Discontinuation of Levaquin® due to adverse drug reactions occurred in 4.3% of patients overall, 3.8% of patients treated with the 250 mg and 500 mg doses and 5.4% of patients treated with the 750 mg dose. The most common adverse drug reactions leading to discontinuation with the 250 and 500 mg doses were gastrointestinal (1.4%), primarily nausea (0.6%); vomiting (0.4%); dizziness (0.3%); and headache (0.2%). The most common adverse drug reactions leading to discontinuation with the 750 mg dose were gastrointestinal (1.2%), primarily nausea (0.6%), vomiting (0.5%); dizziness (0.3%); and headache (0.3%).

Adverse reactions occurring in ≥1% of Levaquin®-treated patients and less common adverse reactions, occurring in 0.1 to <1% of Levaquin®-treated patients, are shown in Table 6 and Table 7, respectively. The most common adverse drug reactions (≥3%) are nausea, headache, diarrhea, i

Lacosamide

Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: (R)-2-acetamido-N-benzyl-3-methoxypropionamide
Molecular Formula: C₁₃H₁₈N₂O₃
CAS Number: 175481-36-4
Brands: Vimpat

REMS:

FDA approved a REMS for lacosamide to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Anticonvulsant; a functionalized amino acid.^{1 4 5 6 22 23 34}

Uses for Lacosamide

Seizure Disorders

Management (in combination with other anticonvulsants) of partial-onset seizures in patients ≥17 years of age with epilepsy.^{1 2 3 4 20 24 36}

IV lacosamide is used as a short-term alternative to oral therapy in patients in whom oral administration of the drug is temporarily not feasible (e.g., patients undergoing surgical procedures, those experiencing difficulty swallowing, those with acute GI disorders).^{1 20 24 36}

Neuropathic Pain

Oral lacosamide has been studied in the treatment of pain associated with diabetic peripheral neuropathy (DPN)† in several short- and long-term clinical trials; additional controlled trials needed to confirm efficacy and safety.^{14 15 16 17 18 38 43}

Lacosamide Dosage and Administration

General

• 
  

  Do not discontinue lacosamide abruptly; withdraw gradually (e.g., gradually discontinue therapy over ≥1 week and/or taper the daily dosage by 200 mg each week) to minimize the potential for increased seizure frequency in patients with seizure disorders.^{1 37}

  
  


• 
  

  Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.^{1 9 10 11 12} (See Suicidality Risk under Cautions.)

  
  

Administration

Administer orally or by IV infusion.¹ The 30- and 60-minute IV infusions are bioequivalent to the oral tablets.¹

Oral Administration

Administer twice daily without regard to food.¹

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.¹

Discard any unused portion of the injection.¹

Dilution

Lacosamide injection may be administered without further dilution or may be diluted with 5% dextrose, lactated Ringer's, or 0.9% sodium chloride injection.¹

Rate of Administration

Administer over 30–60 minutes.¹

Shorter IV infusion times (e.g., over 10 and 15 minutes)† have been used safely in a limited number of patients in clinical trials; further clinical experience is needed to confirm safety.^{24 36 40 41}

Dosage

Adults

Seizure Disorders

Partial Seizures

Oral or IV

Initiate treatment with either oral or IV therapy.¹ Use IV lacosamide if oral administration is temporarily not feasible.^{1 20 24 36}

Patients ≥17 years of age: Initially, 100 mg daily (given as 50 mg twice daily).¹ Based on clinical response and tolerability, may increase dosage in increments of 100 mg daily (given in 2 divided doses) at weekly intervals until the recommended maintenance dosage of 200–400 mg daily is achieved.¹

In clinical trials, an oral dosage of 600 mg daily was not more effective than 400 mg daily and was associated with a substantially higher incidence of adverse effects.¹

Conversion from Oral to IV Therapy

Initial IV dosage should be equivalent to the total daily dosage and frequency of oral lacosamide.¹ There is experience with twice-daily IV infusions for up to 5 days.^{1 24 36}

Conversion from IV to Oral Therapy

At the end of the IV treatment period, may switch to oral administration at the equivalent daily dosage and frequency of the IV administration.¹

Neuropathic Pain†

Pain Associated with Diabetic Peripheral Neuropathy†

Oral

Initial dosage of 100 mg daily (given as 50 mg twice daily) usually has been used in clinical trials, with subsequent weekly increases to reach maintenance dosages of 400–600 mg daily (given as 200–300 mg twice daily) based on individual patient response and tolerability.^{14 15 16 17 18 38}

Prescribing Limits

Adults

Seizure Disorders

Partial Seizures

Oral

Dosages of 600 mg daily were not more effective than 400 mg daily and were associated with a substantially higher incidence of adverse effects.¹

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Titrate dosage with caution; maximum dosage of 300 mg daily is recommended.¹ During dosage titration, closely monitor patients with coexisting hepatic and renal impairment.¹ (See Special Populations under Pharmacokinetics.)

Severe hepatic impairment: Use is not recommended.¹ (See Special Populations under Pharmacokinetics.)

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment is not necessary.¹ (See Special Populations under Pharmacokinetics.)

Severe renal impairment (Cl_Cr ≤30 mL/minute) or end-stage renal disease: Manufacturer recommends a maximum dosage of 300 mg daily.¹ In patients undergoing hemodialysis, consider dosage supplementation of up to 50% following hemodialysis.¹ (See Special Populations under Pharmacokinetics.)

Titrate dosage with caution in patients with any degree of renal impairment.¹ During dosage titration, closely monitor patients with coexisting hepatic and renal impairment.¹

Geriatric Patients

Dosage adjustment not necessary; however, manufacturer recommends cautious dosage titration.¹ (See Special Populations under Pharmacokinetics.)

Cautions for Lacosamide

Contraindications

• 
  

  No known contraindications in the US.¹ In the European Union, contraindicated in patients with hypersensitivity to lacosamide or any ingredient in the formulation and in patients with known second- or third-degree AV block.³⁷

  
  

Warnings/Precautions

Sensitivity Reactions

Multiorgan Hypersensitivity Reactions

One case of symptomatic hepatitis and nephritis, consistent with a delayed multiorgan hypersensitivity reaction, reported in a healthy individual 10 days after discontinuing lacosamide;¹ full recovery occurred within 1 month without specific treatment.¹ Additional cases of possible multiorgan hypersensitivity reaction include 2 cases with rash and elevated hepatic enzyme concentrations and 1 case with myocarditis and hepatitis of uncertain etiology.¹

Multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms or DRESS) also reported with other anticonvulsants; clinical presentation is variable but typically includes fever and rash associated with other organ system involvement (e.g., eosinophilia, hepatitis, nephritis, lymphadenopathy, myocarditis).¹

If a multiorgan hypersensitivity reaction is suspected, discontinue lacosamide and initiate alternative therapy.¹

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).^{1 9 10 11 12} Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.^{9 10 11} Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.^{1 9 10 11}

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.^{1 9 10 11 12} Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.¹⁰

Balance risk of suicidality with the risk of untreated illness.^{1 10} Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.^{1 12} If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.^{1 12} (See Advice to Patients.)

Dizziness and Ataxia

Dizziness and ataxia reported in 25 and 6%, respectively, of patients with partial-onset seizures receiving lacosamide 200–400 mg daily and 1–3 concomitant anticonvulsants compared with 8 and 2%, respectively, of placebo recipients; dizziness was the adverse effect most frequently leading to drug discontinuance (3%).¹

The onset of dizziness and ataxia was most commonly observed during dosage titration.¹ Incidence was substantially increased at dosages >400 mg daily.¹ (See Advice to Patients.)

PR-Interval Prolongation

Dose-dependent increases in PR interval observed in patients and healthy individuals receiving lacosamide.^{1 2 4 5 13 19 20 24 43} At steady state, the timing of the maximum observed mean PR interval coincided with peak plasma lacosamide concentrations.¹

Asymptomatic, first-degree AV block observed in 0.4 or 0.5% of lacosamide-treated patients with partial-onset epilepsy or diabetic neuropathy, respectively, compared with none of the placebo recipients.^{1 2 20}

When lacosamide is given with other drugs that prolong the PR interval, further PR prolongation is possible.^{1 23 37} (See Drugs that Prolong PR Interval under Interactions.)

Use lacosamide with caution in patients with known cardiac conduction abnormalities (e.g., marked first-degree AV block, second- or third-degree AV block, sick sinus syndrome without a pacemaker) or severe cardiovascular disease (e.g., myocardial ischemia, heart failure).^{1 23} The manufacturer recommends obtaining an ECG before initiating lacosamide and after titration to steady state in such patients.¹

Atrial Fibrillation and Atrial Flutter

Lacosamide may predispose patients, particularly those with diabetic neuropathy and/or cardiovascular disease, to develop atrial arrhythmias (i.e., atrial fibrillation or flutter).¹ Atrial fibrillation or flutter reported in 0.5 or 0% of patients receiving lacosamide or placebo, respectively, in diabetic neuropathy studies; no cases of atrial fibrillation or flutter reported in epilepsy studies.¹ (See Advice to Patients.)

Syncope

Syncope or loss of consciousness reported in 1.2 or 0% of patients receiving lacosamide or placebo, respectively, in short-term diabetic neuropathy trials.¹ No increase in syncope observed in short-term, controlled trials in epilepsy patients without significant systemic illness.¹

Most cases of syncope occurred with dosages >400 mg daily.¹ The cause was not determined in most cases; however, several cases were associated with orthostatic changes in BP, atrial fibrillation/flutter (and associated tachycardia), or bradycardia.¹ (See Advice to Patients.)

Discontinuance of Anticonvulsants

Abrupt withdrawal of anticonvulsants may result in increased seizure frequency in patients with seizure disorders.¹ Withdraw lacosamide gradually (e.g., over ≥1 week).¹ (See General under Dosage and Administration.)

Specific Populations

Pregnancy

Category C.¹

UCB AED Pregnancy Registry (for clinicians and patients) at 888-537-7734.¹ North American Antiepileptic Drug (NAAED) Pregnancy Registry (for patients) at 888-233-2334 or .¹

Effect on labor and delivery is unknown.¹

Lacosamide produced developmental toxicity (i.e., increased embryofetal and perinatal mortality, growth deficit) when given to pregnant animals.¹ Developmental neurotoxicity was observed in animals given lacosamide during a period of postnatal development corresponding to the third trimester of human pregnancy.¹ Effects were observed at dosages associated with clinically relevant plasma exposures.¹

Lactation

Lacosamide and/or its metabolites are distributed into milk in rats.¹ Unknown if lacosamide is distributed into human milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

The manufacturer in the US states that safety and efficacy of oral and IV lacosamide have not been established in pediatric patients <17 years of age.¹ However, the drug has been used in pediatric patients ≥16 years of age in some clinical studies⁴ and is approved for such use in the European Union.^{29 37}

Lacosamide interfered with activity of collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axonal outgrowth, in some in vitro studies; potential adverse effects on CNS development cannot be ruled out.¹ (See Actions.)

Decreased brain weights and long-term neurobehavioral changes (e.g., altered open field performance, deficits in learning and memory) reported in rats given lacosamide during neonatal and juvenile periods of postnatal development.¹

Geriatric Use

Insufficient experience in geriatric patients to adequately assess the drug's efficacy in this population.¹ (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use is not recommended in patients with severe hepatic impairment.^{1 21} In patients with mild or moderate hepatic impairment, titrate dosage with caution.¹ During dosage titration, closely monitor patients with coexisting hepatic and renal impairment.¹ (See Hepatic Impairment under Dosage and Administration and see also Special Populations under Pharmacokinetics.)

Renal Impairment

Titrate dosage with caution.¹ During dosage titration, closely monitor patients with coexisting hepatic and renal impairment.¹ (See Renal Impairment under Dosage and Administration and see also Special Populations under Pharmacokinetics.)

Common Adverse Effects

With oral lacosamide for partial-onset seizures: Dizziness,^{1 2 3 4 13 14 15 16} headache,^{1 4 13 14 15 16} diplopia,^{1 3 4 13} nausea,^{1 2 3 4 14 16} vomiting,^{1 2 3 4 13} fatigue,^{1 4 13 15 16} blurred vision,^{1 3 13} ataxia,^{1 2} somnolence,¹ tremor,^{1 3 15 16} nystagmus,^{1 2 3} memory impairment,¹ balance disorder,¹ vertigo,^{1 4} diarrhea.^{1 14}

With short-term IV lacosamide therapy for partial-onset seizures: Systemic adverse effects similar to those observed with oral therapy, local adverse effects (injection site pain or discomfort, irritation, and erythema).^{1 8 24 36}

Interactions for Lacosamide

Metabolized by CYP2C19.¹ Relative contribution of other CYP isoenzymes or non-CYP enzymes in the metabolism of lacosamide is unclear.¹

Does not substantially induce CYP isoenzymes 1A2, 2B6, 2C9, 2C19, or 3A4 in vitro.^{1 19 37}

Does not substantially inhibit CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4, or 3A5 at plasma concentrations observed in clinical studies.^{1 19 37} In vitro data suggest that lacosamide may inhibit CYP2C19 at therapeutic concentrations; however, in vivo data (with omeprazole) suggested minimal or no inhibition (see Specific Drugs under Interactions).^{1 19}

Does not inhibit and is not a substrate of the P-glycoprotein transport system.^{1 37}

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potential for pharmacokinetic drug interactions generally appears to be low.^{1 4 19 26 37}

In vitro data suggest that lacosamide may inhibit CYP2C19 at therapeutic concentrations; however, an in vivo study with omeprazole did not show an inhibitory effect (see Specific Drugs under Interactions).^{1 19}

Drugs Affecting or Affected by P-glycoprotein Transport

Pharmacokinetic interactions unlikely.^{1 37}

Drugs that Prolong PR Interval

Potential pharmacodynamic interaction (additive effect on PR-interval prolongation).^{1 23 37 39 42} (See PR-Interval Prolongation under Cautions and see also Specific Drugs under Interactions.)

Protein-bound Drugs

Clinically relevant pharmacokinetic interactions unlikely.^{1 16 37}

Specific Drugs

Drug	Interaction	Comments
Alcohol	No data currently available37 41
β-adrenergic blocking agents	Potential additive effect on PR-interval prolongation1 13 23
Calcium-channel blocking agents	Potential additive effect on PR-interval prolongation1 23
Carbamazepine	No change in pharmacokinetics of either drug in healthy individuals1 In patients with partial-onset seizures, no change in steady-state plasma concentrations of carbamazepine and its epoxide metabolite1 Small (15–20%) reductions in plasma lacosamide concentrations observed during concurrent administration of carbamazepine, phenobarbital, or phenytoin in population pharmacokinetic studies in patients with partial-onset seizures1 19 20 37 Potential additive effect on PR-interval prolongation; however, subgroup analysis did not reveal an increased magnitude of PR prolongation during concurrent administration1 23 37
Clonazepam	No change in steady-state plasma clonazepam concentrations1 22
Digoxin	Lacosamide did not alter digoxin pharmacokinetics in healthy individuals1 22 37 Potential additive effect on PR-interval prolongation1 23 42
Gabapentin	No change in steady-state gabapentin concentrations1 22
Lamotrigine	No change in steady-state lamotrigine concentrations1 22 Potential additive effect on PR-interval prolongation; however, subgroup analysis did not reveal an increased magnitude of PR prolongation during concurrent administration1 23 37
Levetiracetam	No change in steady-state levetiracetam concentrations1 22
Metformin	No clinically important changes in metformin concentrations1 22 Metformin did not alter lacosamide pharmacokinetics1
Omeprazole	Lacosamide did not alter pharmacokinetics of single-dose omeprazole in healthy individuals1 Omeprazole reduced plasma concentrations of lacosamide's inactive O-desmethyl metabolite by about 60%1
Oral contraceptives	Ethinyl estradiol/levonorgestrel: No substantial change in pharmacodynamics and pharmacokinetics of the oral contraceptive; small (20%) increase in peak plasma ethinyl estradiol concentrations1 22 37
Oxcarbazepine	No change in steady-state concentrations of oxcarbazepine's active monohydroxy metabolite (MHD)1 22
Phenobarbital	No change in steady-state plasma phenobarbital concentrations1 22 Small (15–20%) reductions in plasma lacosamide concentrations observed during concurrent administration of carbamazepine, phenobarbital, or phenytoin in population pharmacokinetic studies in patients with partial-onset seizures1 19 20 37
Phenytoin	No change in steady-state plasma phenytoin concentrations1 Small (15–20%) reductions in plasma lacosamide concentrations observed during concurrent administration of carbamazepine, phenobarbital, or phenytoin in population pharmacokinetic studies in patients with partial-onset seizures1 19 20 37
Pregabalin	Potential additive effect on PR-interval prolongation1 37 39
Topiramate	No change in steady-state plasma topiramate concentrations1
Valproic Acid	No change in pharmacokinetics of either drug in healthy individuals1 In patients with partial-onset seizures, no change in steady-state plasma concentrations of valproic acid1
Zonisamide	No change in steady-state plasma zonisamide concentrations1

Lacosamide Pharmacokinetics

Absorption

Pharmacokinetics of oral and IV lacosamide are generally dose-proportional over a range of 100–800 mg.^{1 19}

Bioavailability

Oral bioavailability is approximately 100%.¹ Peak plasma lacosamide concentrations attained within 0.5–4 hours after oral administration.^{1 8 22} Peak plasma concentrations of inactive O-desmethyl metabolite attained within 0.5–12 hours after oral administration.¹

Lacosamide 30- and 60-minute IV infusions are bioequivalent to the oral tablet.¹ Peak plasma concentrations reached at end of infusion.¹

Food

Food does not affect rate or extent of absorption.¹

Distribution

Extent

Lacosamide and/or metabolites distribute into milk in rats; unknown if distributed into human milk.¹

Plasma Protein Binding

<15%.¹

Elimination

Metabolism

Metabolized by CYP2C19; effect of other CYP isoenzymes or non-CYP enzymes in the metabolism of lacosamide is unclear.¹

Elimination Route

Eliminated primarily by renal excretion and biotransformation.^{1 19} Following oral and IV administration of a 100-mg radiolabeled dose, approximately 95% of the dose was recovered in urine and <0.5% was recovered in feces; the principal compounds excreted were unchanged lacosamide (approximately 40%), O-desmethyl-lacosamide (approximately 30%; inactive metabolite), and a structurally unknown polar fraction (approximately 20%; possibly serine derivatives).^{1 37}

Half-life

Lacosamide: Approximately 12–13 hours.^{1 19 22}

O-desmethyl metabolite: 15–23 hours.¹

Special Populations

In individuals with mild or moderate renal impairment, AUC is increased by approximately 25%.^{1 41} In individuals with severe renal impairment, AUC is increased by approximately 60%.^{1 41} However, peak plasma concentrations were unaffected.^{1 41} A 4-hour hemodialysis session reduces the AUC by approximately 50%.¹

Individuals with moderate hepatic impairment (Child-Pugh class B) had higher plasma concentrations of lacosamide (approximately 50–60% higher AUCs) compared with healthy individuals.¹ Pharmacokinetics not specifically evaluated in individuals with severe hepatic impairment.¹

In geriatric individuals, AUCs and peak plasma concentrations (normalized for dosage and body weight) were approximately 20% higher compared with younger individuals, possibly related to differences in total body water and age-associated reductions in renal clearance.¹

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).¹

Parenteral

Injection for IV Infusion

20–25°C (may be exposed to 15–30°C).¹

Discard any unused portion of the injection.¹

When stored in glass or PVC bags at 15–30°C, injection that has been diluted with 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer's injection is stable for ≥24 hours.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible1
Dextrose 5% in water
Ringer's injection, lactated
Sodium chloride 0.9%

Actions

• 
  

  Exact mechanism(s) of anticonvulsant and antinociceptive action is unknown.^{1 2 4 5 7 8 14 15 16 19 21 22 25 26 27 41}

  
  


• 
  

  In vitro electrophysiologic studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, which results in stablilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.^{1 2 4 5 7 8 16 19 22 25 27}

  
  


• 
  

  In some preclinical tests, lacosamide was found to bind to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein that is mainly expressed in the nervous system and involved in neuronal differentiation, polarization, gene expression, and control of axonal outgrowth.^{1 7 8 13 16 25 27 28 30} It was suggested that this binding may contribute to the anticonvulsant and antinociceptive activity of the drug.^{1 7 8 13 16 25 27 28 30} However, binding was not confirmed in subsequent tests.⁴¹

  
  


• 
  

  Does not exhibit binding affinity for GABA, N-methyl-D-aspartic acid (NMDA), adenosine, muscarinic, serotonin, histamine, dopamine, or other receptors.^{14 20 26} Does not affect reuptake or metabolism of norepinephrine, dopamine, serotonin, or GABA.^{6 7 20 26} Does not affect voltage-activated calcium channels (L-, –, P/Q-, or T-type) or voltage-activated potassium channels and does not modulate delayed-rectifier or A-type potassium currents.^{6 20 22 26}

  
  

Advice to Patients

• 
  

  Importance of providing copy of written patient information (medication guide) each time lacosamide is dispensed; importance of patient reading this information prior to taking the drug.¹

  
  


• 
  

  Risk of suicidality (anticonvulsants, including lacosamide, may increase risk of suicidal thoughts or actions in about 1 in 500 people).^{1 10 12} Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).^{1 10}

  
  


• 
  

  Importance of taking lacosamide only as prescribed.¹

  
  


• 
  

  Risk of dizziness, drowsiness, blurred vision, or problems with coordination and balance.^{1 6 35} Importance of advising patients not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects.^{1 35 37}

  
  


• 
  

  Risk of dizziness, lightheadedness, fainting, or irregular heart beat, particularly in patients with underlying cardiovascular disease or cardiac conduction abnormalities and in those taking drugs that affect the heart.^{1 35} These symptoms are more likely to occur when rising quickly from a recumbent position.³⁵ Importance of advising patients to lie down with their legs raised until they feel better if such symptoms develop and to contact their clinician promptly.^{1 35} Importance of patients also being aware of possible symptoms of cardiac rhythm and conduction abnormalities (e.g., atrial fibrillation and flutter), including palpitations, rapid heart beat, and shortness of breath; importance of patients contacting their clinician should any of these symptoms occur.¹

  
  


• 
  

  Risk of serious hypersensitivity reactions affecting multiple organs (e.g., liver, kidney); lacosamide should be discontinued if serious hypersensitivity reactions are suspected.¹ Importance of informing patients to contact their clinician promptly if symptoms suggestive of liver damage occur (e.g., fatigue, jaundice, dark urine).¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 35} Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Cautions).¹

  
  


• 
  

  Importance of informing patients not to stop taking lacosamide without first talking to their clinician since stopping the drug suddenly can cause serious problems, including seizures.^{1 35}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illness (e.g., heart disease, kidney disease, liver disease, depression, bipolar disorder) or family history of suicidality or bipolar disorder.^{1 35}

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule V (C-V) drug.

Lacosamide

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	50 mg	Vimpat (C-V)	UCB
		100 mg	Vimpat (C-V)	UCB
		150 mg	Vimpat (C-V)	UCB
		200 mg	Vimpat (C-V)	UCB
Parenteral	Injection, for IV infusion	10 mg/mL	Vimpat (C-V; available in single-use glass vials)	UCB

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Vimpat 100MG Tablets (SCHWARZ PHARMA): 60/$415.97 or 180/$1,185.98

Vimpat 150MG Tablets (SCHWARZ PHARMA): 60/$439.99 or 180/$1,260.02

Vimpat 200MG Tablets (SCHWARZ PHARMA): 60/$439.97 or 180/$1,259.96

Vimpat 50MG Tablets (SCHWARZ PHARMA): 60/$265.98 or 180/$749.95

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. UCB, Inc. Vimpat (lacosamide) tablets and injection for intravenous use prescribing information. Smyrna, GA; 2009 Jan.

2. Ben-Menachem E, Biton V, Jatuzis D et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007; 48:1308-17. [PubMed 17635557]

3. Chung S, Sperling M, Biton V et al. Lacosamide: efficacy and safety as oral adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007; 48 (Suppl. 7):57. Abstr. No. 065.

4. Halász P, Kälviäinen R, Mazurkiewicz-Beldzinska M et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia. 2009; 50:443-53. [PubMed 19183227]

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