Download NAME: Carbamazepine (Tegretol)

NAME: Carbamazepine (Tegretol)
MOA: Chemically related to imipramine; reduces polysynaptic responses, blocks post-tetanic potentiation, and may depress thalamic
potential possibly by inhibiton of voltage gated sodium channels
Efficacy (Indication/Use):
-
FDA indications: Epilepsy, Partial, generalized, and mixed types of seizures
Should be considered first line therapy for newly diagnosed partial seizures and in generalized convulsive seizures
SAFETY:
Adverse Effects: DIPLOPIA, dizziness, HYPONATREMIA (SIADH), blood dyscrasias, lethargy
Major Drug Interactions: any drug that inhibit or induces CYP 3A4
Contraindications:
- concomitant use of monoamine oxidase inhibitors
- hypersensitivity to carbamazepine or tricyclic compounds
- history of previous bone marrow depression
Precautions:
- breast feeding
- do not discontinue abruptly
- elderly patients
- increased intraocular pressure
- kidney dysfunction and liver dysfunction
- patients with underlying mental illness may experience activation of latent psychosis or agitation
- pregnancy (especially the first trimester)
Pregnancy Category: D
Kinetics:
-
-
Food may enhance bioavailability
Absorbtion from IR tablets is slow and inconsistent due to poor water solubility
Suspension absorbed faster than tablets
Controlled release formulations dosed twice daily are bio-equivalent with QID IR dosing and provide lower peaks &
higher troughs
Tegretol XR should be taken with food; drug casing will be excreted in feces
Metabolized by the liver, primarily by CYP-3A4
Induces own metabolism; AUTOINDUCTION begins within 3-5 days and takes 21-35 days to completely level off
Therapeutic range  4 to 12 mcg/mL
Dosage & Administration
Initial: 200 mg twice daily (tablets, extended release tablets, or extended release capsules) or 100 mg of suspension 4 times/day
(400 mg daily); increase by up to 200 mg/day at weekly intervals using a twice daily regimen of extended release tablets or capsules, or a
3-4 times/day regimen of other formulations until optimal response and therapeutic levels are achieved; usual dose: 800-1200 mg/day;
some patients have required up to 1.6-2.4 g/day
Monitoring
CBC with platelet count, reticulocytes, serum iron, lipid panel, liver function tests, urinalysis, BUN, serum carbamazepine levels,
thyroid function tests, serum sodium; ophthalmic exams (pupillary reflexes); observe patient for excessive sedation, especially when
instituting or increasing therapy
References (Guidelines, Drug Info Sources)
http://www.thomsonhc.com.db.usip.edu/hcs/librarian/ND_PR/Main/SBK/1/PFPUI/Hy3XhRC1syYGxd/ND_PG/PRIH/CS/DE6542/ND_T
/HCS/ND_P/Main/DUPLICATIONSHIELDSYNC/552D96/ND_B/HCS/PFActionId/hcs.common.RetrieveDocumentCommon/DocId/010
3/ContentSetId/31/SearchTerm/carbamazepine/SearchOption/BeginWith#secN66838 (Accessed 8/16/06)
Lexi-Comp On-line. Carbamazepine. Updated 8/11/06; Accessed 8/16/06; http://www.crlonline.com/crlsql/servlet/crlonline
Garnett W. Gidal BE. Epilepsy. In Pharmacotherapy: A Pathophysiologic Approach Sixth Ed. Editors: DiPiro JT. Talbert RL. Yee GC.
Matzke GR. Wells BG. Posey LM. 2005. New York. pgs 1023-1048.
NAME: Phenytoin (Dilantin)
MOA:
- Primary site of action is in motor cortex; stabilizes the threshold against hyperexcitability.
-Alteration of ion fluxes associated with depolarization, repolarazation and membrane stability; alteration of Ca++ uptake in
presynaptic terminals and influence on Ca++ dependent synaptic neurotransmitter release; alteration of Na+/K+ ATP-dependent
ionic membrane pump.
Place in Therapy:
- FDA approved indications: complex partial seizures, tonic-clonic seizures, seizure prophylaxis during neurosurgery
- First line agent for primary generalized convulsive and partial seizures. Also a first line agent for treatment of status
epilepticus.
SAFETY:
Adverse Effects: Behavior changes, skin thickening, GINGIVAL HYPERPLASIA, HIRSUTISM, coarsening of facial hair, acne,
blood dyscasias, rash, ataxia, NYSTAGMUS, dizziness, VISUAL BLURRING
Major Drug Interactions:
- Phenytoin levels may be increased by many drugs that displace it from albumin, or inhibit its metabolism: allopurinol,
amiodarone, calcium channel blockers, cimetidine, fluconzole, gemfibrozil, isoniazid, ketoconazole, NSAIDs,
methylphenidate, metronidazole, omeprazole, salicylates, SSRIs, sulfonamides, ticlopidine, TCAs, trazadone,
trimethoprim, etc.
Contraindications:
- Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation
- Pregnancy
Precautions:
- alcohol use (acute use: increases levels; chronic use: decreases levels)
- avoid abrupt withdrawal (may precipitate status epilepticus)
- diabetes mellitus (hyperglycemia has occurred in diabetics)
- discontinue if skin rash occurs (do not resume if rash is exfoliative, purpuric, or bullous, or if lupus erythematosus or
Stevens-Johnson syndrome is suspected)
- impaired liver function
- patients with a history of renal or liver disease should not receive the oral loading dose regimen
- pregnancy
Pregnancy Category: D
Kinetics:
-
Metabolized by the liver via CYP 2C9 and CYP 2C19
Therapeutic range between 10-20 mcg/ml
Usual unbound concentrations associated with optimal therapy being between 1 to 2 mcg/ml
Levels peak between 4 – 8 hours after dose
Therapeutic range of phenytoin is based on conditions of normal protein binding
o Phenytoin is 90-95% bound to albumin
In states of decreased protein binding, the observed level is falsely decreased, so either the therapeutic range or the
observed concentration must be adjusted.
o A more common approach is to correct the observed concentration
 Hypoalbuminemia
Corrected Level =
(measured concentration) 1
[(0.2)(measured albumin) + 0.1]
 Renal Failure (CrCl < 10mL/min)
Corrected Level =
(measured concentration) 1
[(0.1)(measured albumin) + 0.1]
Hypoalbuminemia
Renal Failure
Measured
Concentration
Measured
Albumin
Corrected
Level
Measured
Concentration
Measured
Albumin
Corrected
Level
5 mcg/mL
5 mcg/mL
5 mcg/mL
5 mcg/mL
10 mcg/mL
10 mcg/mL
10 mcg/mL
10 mcg/mL
3.5 g/dL
3 g/dL
2.5 g/dL
2 g/dL
3.5 g/dL
3 g/dL
2.5 g/dL
2 g/dL
6 mcg/mL
7 mcg/mL
8 mcg/mL
10 mcg/mL
13 mcg/mL
14 mcg/mL
17 mcg/mL
20 mcg/mL
5 mcg/mL
5 mcg/mL
5 mcg/mL
5 mcg/mL
10 mcg/mL
10 mcg/mL
10 mcg/mL
10 mcg/mL
3.5 g/dL
3 g/dL
2.5 g/dL
2 g/dL
3.5 g/dL
3 g/dL
2.5 g/dL
2 g/dL
11 mcg/mL
13 mcg/mL
14 mcg/mL
17 mcg/mL
22 mcg/mL
25 mcg/mL
29 mcg/mL
33 mcg/mL
15 mcg/mL
15 mcg/mL
15 mcg/mL
15 mcg/mL
3.5 g/dL
3 g/dL
2.5 g/dL
2 g/dL
19 mcg/mL
21 mcg/mL
25 mcg/mL
30 mcg/mL
15 mcg/mL
15 mcg/mL
15 mcg/mL
15 mcg/mL
3.5 g/dL
3 g/dL
2.5 g/dL
2 g/dL
33 mcg/mL
38 mcg/mL
43 mcg/mL
50 mcg/mL
Dosage & Administration
- Food increases the absorption of phenytoin
- May dose QD or up to QID
- Empiric dosing:
o
o
o
Monitoring
-
IV loading dose: 10 – 15 mg/kg (infused 25-50 mg/min)
PO loading dose: 15 – 20 mg/kg in 3 divided doses every 2-4 hrs
Maintenance dose: 5 – 7 mg/kg/day (begin 12 hrs after LD)
Plasma phenytoin level and decrease in seizure frequency
For toxic effects, monitor blood sugar levels, neurological function, hepatic function, plasma albumin
References (Guidelines, Drug Info Sources)
http://www.thomsonhc.com.db.usip.edu/hcs/librarian/ND_PR/Main/SBK/2/PFPUI/q13GLHS1szV0pI/ND_PG/PRI
H/CS/B625F1/ND_T/HCS/ND_P/Main/DUPLICATIONSHIELDSYNC/C12500/ND_B/HCS/PFActionId/hcs.com
mon.RetrieveDocumentCommon/DocId/0031/ContentSetId/31/SearchTerm/Phenytoin%20/SearchOption/BeginWit
h#secN104992 (accessed on 8/17/06)
Lexi-Comp On-line.Phenytoin. Updated 8/14/06; Accessed 8/18/06; http://www.crlonline.com/crlsql/servlet/crlonline
Garnett W. Gidal BE. Epilepsy. In Pharmacotherapy: A Pathophysiologic Approach Sixth Ed. Editors: DiPiro JT. Talbert RL. Yee GC.
Matzke GR. Wells BG. Posey LM. 2005. New York. pgs 1023-1048.
NAME: Levetiracetam (Keppra)
MOA:
- The precise mechanism by which levetiracetam exerts its antiepileptic effect is unknown.
- unrelated to other seizure drugs
- However, several studies have suggested the mechanism may involve one or more of the following:
o
o
o
o
inhibition of voltage-dependent N-type calcium channels
blockade of GABA-ergic inhibitory transmission through displacement of negative modulators
reduction of delayed rectifier potassium current
binding to synaptic proteins which modulate neurotransmitter release
Efficacy (Indication/Use):
- FDA Approved Indications: Partial seizure; Adjunct
SAFETY:
Adverse Effects: Sedation, fatigue, co-ordination difficulties, behavior disturbances (agitation, irritability, depression)
Major Drug Interactions: None
Contraindications: hypersensitivity to levetiracetam or any component of the product
Precautions:
- hemodialysis; reduced levels of levetiracetam
- renal impairment; potential toxicity due to total body clearance reductions of 40% (creatinine clearance (Clcr) 50 to 80
mL/min), 50% (Clcr 30 to 50 mL/min), 60% (Clcr less than 30 mL/min), and 70% (anuria)
- sudden withdrawal of therapy; increased seizure frequency possible
- suicides have occurred
Pregnancy Category: C
Kinetics:
-
Negligible protein binding
66% renally clearance; the rest is metabolized in the blood by enzymatic hydrolysis
No therapeutic drug level monitoring
Dosage & Administration
- Initial: 500 mg twice daily; may increase every 2 weeks by 500 mg/dose to a maximum of 1500 mg twice daily. Doses
-
>3000 mg/day have been used in trials; however, there is no evidence of increased benefit.
Renal Impairment
Clcr >80 mL/minute: 500-1500 mg every 12 hours
Clcr 50-80 mL/minute: 500-1000 mg every 12 hours
Clcr 30-50 mL/minute: 250-750 mg every 12 hours
Clcr <30 mL/minute: 250-500 mg every 12 hours
End-stage renal disease patients using dialysis: 500-1000 mg every 24 hours; a supplemental dose of 250-500 mg following dialysis is
recommended
Monitoring
-
Patients should be monitored for a reduction in the frequency and severity of seizures.
Patients receiving levetiracetam should be monitored for signs and symptoms of hypersensitivity to
it.
References (Guidelines, Drug Info Sources)
http://www.thomsonhc.com.db.usip.edu/hcs/librarian/ND_PR/Main/SBK/2/PFPUI/q13GLHS1sAcjcx/ND_PG/PRI
H/CS/F29CF8/ND_T/HCS/ND_P/Main/DUPLICATIONSHIELDSYNC/84FDDF/ND_B/HCS/PFActionId/hcs.co
mmon.RetrieveDocumentCommon/DocId/2017/ContentSetId/31/SearchTerm/levetiracetam/SearchOption/BeginWi
th#secN70574 (accessed 8/18/06)
Lexi-Comp On-line.Keppra. Updated 8/11/06; Accessed 8/18/06; http://www.crlonline.com/crlsql/servlet/crlonline
Garnett W. Gidal BE. Epilepsy. In Pharmacotherapy: A Pathophysiologic Approach Sixth Ed. Editors: DiPiro JT. Talbert RL. Yee GC.
Matzke GR. Wells BG. Posey LM. 2005. New York. pgs 1023-1048.
NAME: Topiramate (Topamax)
MOA:
- Blocks neuronal voltage-dependent sodium channels
- Enhances GABA(A) activity
- Antagonizes AMPA/kainate glutamate receptors
- Weakly inhibits carbonic anhydrase
Efficacy (Indication/Use):
- FDA approved indications: Initial and adjunctive therapy for partial seizures as well as generalized, tonic-clonic seizures
SAFETY:
Adverse Effects: KIDNEY STONES, WEIGHT LOSS, PSCHOMOTOR SLOWING, ACUTE ANGLE GLAUCOMA,
OLIGOHYDROSIS (decreased sweating; heat intolerance; hyperthermia) , METABOLIC ACIDOSIS(non-anion gap; decreases
serum bicarbonate), somnolence, fatigue, headache, dizziness
Major Drug Interactions:
- May increase phenytoin and haldol concentrations
- May decrease birth control, digoxin, lithium
Contraindications: Hypersensitivity to topiramate or any component of its formulation
Precautions:
- Behavioral disorders or cognitive deficits
- Concomitant use of topiramate with valproic acid (associated with hyperammonemia with or without encephalopathy)
-
Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus,
diarrhea, surgery, ketogenic diet or drugs)
- Paresthesia
- Renal or hepatic impairment
- Withdraw gradually to avoid increased seizure frequency
Pregnancy Category: C
Kinetics:
- No significant protein binding
- 40-70% of dose is excreted unchanged in urine
- Fraction of drug is hepatically metabolized, which would be increased by enzyme inducing drugs
- T ½ is 15-23 hours
Dosage & Administration
- Take with or with out food
- Partial onset seizures: Initial: 25-50 mg/day (given in 2 divided doses) for 1 week; increase at weekly intervals by 25-50
-
Monitoring
-
mg/day until response; usual maintenance dose: 100-200 mg twice daily. Doses >1600 mg/day have not been studied.
Primary generalized tonic-clonic seizures: Use initial dose as listed above for partial onset seizures, but use slower initial
titration rate; titrate upwards to recommended dose by the end of 8 weeks; usual maintenance dose: 200 mg twice daily.
Doses >1600 mg/day have not been studied.
Therapeutic
o A reduction in seizure frequency and severity is indicative of therapeutic response to topiramate
Toxic
o Baseline and periodic serum bicarbonate levels during treatment
o Renal function in the elderly
o Body weight
o Clinical evidence of cognitive dysfunction (memory impairment, poor judgement, confusion
o Clinical evidence of acute or chronic metabolic acidosis, such as hyperventilation, fatigue, anorexia, cardiac
arrhythmias or stupor.
o Hyperammonemia signs and symptoms
References (Guidelines, Drug Info Sources)
http://www.thomsonhc.com.db.usip.edu/hcs/librarian/ND_PR/Main/SBK/1/PFPUI/q13GLHS1sAlTuy/ND_PG/PRI
H/CS/3A970B/ND_T/HCS/ND_P/Main/DUPLICATIONSHIELDSYNC/2EACD1/ND_B/HCS/PFActionId/hcs.co
mmon.RetrieveDocumentCommon/DocId/1742/ContentSetId/31/SearchTerm/topiramate/SearchOption/BeginWith
#secN77375 (accessed 8/17/06)
Lexi-Comp On-line.Topamax. Updated 8/11/06; Accessed 8/17/06; http://www.crlonline.com/crlsql/servlet/crlonline
Garnett W. Gidal BE. Epilepsy. In Pharmacotherapy: A Pathophysiologic Approach Sixth Ed. Editors: DiPiro JT. Talbert RL. Yee GC.
Matzke GR. Wells BG. Posey LM. 2005. New York. pgs 1023-1048.
NAME: Lamotrigine (Lamictal)
MOA:
- Blockade of both voltage-gated and use dependant sodium channels
- Dose dependent inhibition of Ca++ currents (possibly pre-synaptic)
- Blocks release of excitatory amino acid neurotransmitters (glutamate & aspartate)
Efficacy (Indication/Use):
- FDA approved for use in partial seizures (monotherapy and adjunctive)
- Alternative therapy for absence seizures.
SAFETY:
Adverse Effects: RASH (especially with high doses or given with valproic acid), DIPLOPIA, DROWSINESS, ATAXIA,
headache
- ADE’s are more common when given with other AEDs
Major Drug Interactions:
- Other “inducing agents” and oral contraceptives may alter plasma concentrations, reducing lamotigine half life by as
much as 50%
- Valproic acid inhibits the clearance of lamotrigine even if given in small doses
- Lamotigine does not seem to alter the kinetics of any medications
Contraindications: hypersensitivity to lamotrigine or any component of the product
Precautions:
- abrupt drug discontinuation
- d/c therapy at first sign of rash
- fatal hypersensitivity reactions have occurred
- concomitant administration of valproic acid with lamotrigine may increase the risk of Stevens-Johnson syndrome or
other potentially life-threatening rashes
- blood dyscrasias have occurred with therapy
Pregnancy Category: C
Kinetics:
- 98% bioavailabile
- Food has no effect
- Metabolized hepatically via glucuronosyl transferase
- T ½ ~ 24-29 hours
- Clearance is higher in children and lower in the elderly
- No serum concentration established
Dosage & Administration
-Patients receiving AED regimens containing valproic acid: Initial dose: 25 mg every other day for 2 weeks, then 25 mg every
day for 2 weeks. Dose may be increased by 25-50 mg every day for 1-2 weeks in order to achieve maintenance dose. Maintenance dose:
100-400 mg/day in 1-2 divided doses (usual range 100-200 mg/day).
- Patients receiving enzyme-inducing AED regimens without valproic acid: Initial dose: 50 mg/day for 2 weeks, then 100 mg in 2
doses for 2 weeks; thereafter, daily dose can be increased by 100 mg every 1-2 weeks to be given in 2 divided doses. Usual maintenance
dose: 300-500 mg/day in 2 divided doses; doses as high as 700 mg/day have been reported
- Can disperse in juice or water
Monitoring
- Seizure, frequency and duration,
- Serum levels of concurrent anticonvulsants, hypersensitivity reactions, especially rash
References (Guidelines, Drug Info Sources)
http://www.thomsonhc.com.db.usip.edu/hcs/librarian/ND_PR/Main/SBK/1/PFPUI/q13GLHS1sAwGYh/ND_PG/P
RIH/CS/5BBDC5/ND_T/HCS/ND_P/Main/DUPLICATIONSHIELDSYNC/83AF78/ND_B/HCS/PFActionId/hcs.
common.RetrieveDocumentCommon/DocId/1470/ContentSetId/31/SearchTerm/lamotrigine/SearchOption/BeginW
ith#secN74168 (accessed 8/18/06)
Lexi-Comp On-line.Lamictal. Updated 8/11/06; Accessed 8/18/06; http://www.crlonline.com/crlsql/servlet/crlonline
Garnett W. Gidal BE. Epilepsy. In Pharmacotherapy: A Pathophysiologic Approach Sixth Ed. Editors: DiPiro JT. Talbert RL. Yee GC.
Matzke GR. Wells BG. Posey LM. 2005. New York. pgs 1023-1048.