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Fosphenytoin: A feasible alternative to phenytoin for seizure therapy
p p r o x i m a t e l y 400,000 p a t i e n t s w i t h s e i z u r e s r e q u i r e t r e a t m e n t in e m e r g e n c y d e p a r t m e n t s e a c h year. 1 T h u s far, p h e n y t o i n (Dilantin) h a s b e e n o n e of t h e c o r n e r s t o n e s of s e i z u r e therapy. Unfortunately, t h e r e are s e v e r a l c o m p l i c a t i o n s a s s o c i a t e d w i t h t h e a d m i n i s t r a t i o n of p a r e n t e r a l p h e n y t o i n , r e l a t e d to its p r o p y l e n e glycol a n d e t h a n o l b a s e . T h e h i g h l y alkaline p H of 12 is r e s p o n s i b l e for painful infusions, local v e n o u s irritation (phlebitis), i n c o m p a t i b i l i t i e s w i t h m o s t IV s o l u t i o n s o t h e r t h a n n o r m a l saline solution, a n d if infiltration occurs, skin s l o u g h i n g a n d t i s s u e n e c r o s i s , z In addition, h y p o t e n s i o n , c a r d i a c d y s r h y t h m i a s , a n d c a r d i o v a s c u l a r c o l l a p s e are p o s s i ble if p h e n y t o i n is i n f u s e d at a r a t e g r e a t e r t h a n 50 mg/min. F o s p h e n y t o i n (Cerebyx), a r e c e n t l y r e l e a s e d prod r u g formulation of p h e n y t o i n , c o n v e r t s to p h e n y t o i n in t h e body; therefore it h a s t h e s a m e t h e r a p e u t i c a c t i o n as p h e n y t o i n . It b i n d s to p l a s m a p r o t e i n s b u t r a p i d l y e n t e r s all t i s s u e s w h e r e it b i n d s to p r o t e i n s a n d p h o s p h o l i p i d s . B e c a u s e f o s p h e n y t o i n delivers p h e n y t o i n in a w a t e r - s o l u b l e form, m a n y of t h e infus i o n - r e l a t e d a n d c a r d i o v a s c u l a r c o m p l i c a t i o n s are e l i m i n a t e d . 3 In addition, f o s p h e n y t o i n ' s lower p H of 8.5 to 8.8 allows for c o m p a t i b i l i t y w i t h m o s t IV solutions, d o e s n o t r e q u i r e t h e u s e of a filter in a d m i n i s tration, a n d c a n b e i n f u s e d at a faster rate.
A
Dosing and administration F o s p h e n y t o i n is biologically b i o e q u i v a l e n t to p h e n y toin; t h e r e f o r e t h e e f f i c a c y r e m a i n s t h e s a m e . F o s p h e n y t o i n d o s i n g is also e q u i v a l e n t to t h a t of p h e n y t o i n . A s t a n d a r d l o a d i n g d o s e of f o s p h e n y t o i n is 15 to 20 m g / k g , or a b o u t 1200 to 1600 m g for a n 80 Kathleen Bradbury-Golas is a clinical nurse specialist, Critical Care and Medical-Surgical Department, Somers Point, New Jersey. Linda Carson is a staff nurse, Emergency Department, Shore Memorial Hospital, Somers Point, New Jersey. For reprints, write Kathleen Bradbury-Golas, RN, MSN, CNS, C, CCRN, 14 Avalon Woods Court, Swainton, NJ 08210. J Emerg Nurs 1996;22:431-2. Copyright 9 1996 by the Emergency Nurses Association. 0099-1767/96 $5.00 + 0 18/62/76730
k g individual, F o s p h e n y t o i n c a n b e i n f u s e d at a m a x i m u m r a t e of 150 m g / m i n . This m e a n s t h a t a n initial d o s e c a n b e g i v e n over a p p r o x i m a t e l y 8 to 10 minu t e s ( b a s e d on an 80 k g person) c o m p a r e d w i t h t h e 20 to 30 m i n u t e s t y p i c a l l y r e q u i r e d for a s t a n d a r d d o s e of p h e n y t o i n . 1
In addition, f o s p h e n y t o i n c a n be a d m i n i s t e r e d intramuscularly.
In addition, f o s p h e n y t o i n c a n b e a d m i n i s t e r e d i n t r a m u s c u l a r l y if IV a c c e s s is n o t o b t a i n e d or if a t e m p o r a r y s u b s t i t u t e for oral p h e n y t o i n is required. In controlled trials, f o s p h e n y t o i n w a s a d m i n i s t e r e d i n t r a m u s c u l a r l y a s a s i n g l e daily dose, w i t h either one or t w o injection sites. T h e m a n u f a c t u r e r reports t h a t i n j e c t i o n s of 5 to 20 ml at a s i n g l e s i t e w e r e well t o l e r a t e d b y t h e p a t i e n t s p a r t i c i p a t i n g in t h e s e trials. 4 I n t r a m u s c u l a r i n j e c t i o n is n o t r e c o m m e n d e d with phenytoin. 5 F o s p h e n y t o i n is s u p p l i e d in 2 mI (150 mg) a n d 10 ml (750 mg) vials a n d m u s t b e refrigerated until used. If a d m i x e d in a d v a n c e , f o s p h e n y t o i n is stable for 8 hours at room t e m p e r a t u r e or 24 hours if refrigerated. 1 F o s p h e n y t o i n can b e m i x e d for injection to a c o n c e n tration r a n g i n g from 2.5 to 20 mg/ml. For example, it c a n b e m i x e d in 50 to 400 ml of 5% d e x t r o s e in w a t e r or normal saline solution d e p e n d i n g on t h e n e e d e d concentration. Filtering is n o t r e q u i r e d as w i t h p h e n y toin. P h e n y t o i n is s t a b l e at room t e m p e r a t u r e w h e n n o t mixed; however, it c a n n o t b e p r e m i x e d b e c a u s e of its lack of solubility a n d resultant precipitation. Standard laboratory chromatographic assays u s e d to m e a s u r e p h e n y t o i n also are u s e d to a s c e r t a i n t h e r a p e u t i c levels of f o s p h e n y t o i n . However, a 2- to 4-hour w a i t i n g p e r i o d is r e c o m m e n d e d after fosp h e n y t o i n infusion for g r e a t e s t a c c u r a c y .
October 1996 431
JOURNAL OF EMERGENCYNURSING/Bradbury-Golasand Carson
Table 1 Comparison of phenytoin and fosphenytoin 1"~ Phenytoin
Propylene glycol/ethanol base pH of 12 Compatible with NSS only; precipitation can occur IV filter required IM injection not recommended Maximum IV rate of 50 mg/min Cardiac monitoring required Side effects Pain and burning at IV infusion site Vein irritation Potential necrosis Hypotension Dysrhythmias Potential cardiac arrest Stability Unmixed: Stable at room temperature Premixed: Unable to premix because of rapid precipitation Therapeutic levels: Wait 1 to 2 hours before obtaining blood specimen
Fosphenytoin
No propylene glycol/ethanol base; water-soluble pH 8.5 to 8.8 Compatible with common IV solutions; no precipitation No filter required Well absorbed IM IV rate of 150 mg/min Cardiac monitoring required (IV only) Side effects Minimal infusion complications Paresthesia Pruritis Infrequent hypotension Infrequent dysrhythmias Infrequent cardiac arrests Stability Unmixed: Stable without refrigeration for 48 hours Premixed: Stable with refrigeration for 24 hours Therapeutic levels: Wait 2 to 4 hours before obtaining blood specimen
NSS, Normal saline solution; IM, intramuscular.
S i d e effects
Side effects of f o s p h e n y t o i n are similar to those of p h e n y t o i n b u t far less frequent. There also m a y b e t r a n s i e n t p a r e s t h e s i a a n d pruritis, primarily in t h e p e r i n e a l area, w h i c h usually resolves s p o n t a n e o u s l y after c o m p l e t i o n of t h e infusion. The i n t e n s i t y of the p a r e s t h e s i a a n d pruritis is rate related. With IV a d m i n i s t r a t i o n t h e rate c a n b e d e c r e a s e d to r e d u c e t h e effects. More s e r i o u s side effects i n c l u d i n g h y p o t e n s i o n , d y s r h y t h m i a s , a n d cardiac arrest have b e e n reported. However, the i n c i d e n c e of t h e s e side effects is lower for f o s p h e n y t o i n t h a n w i t h p h e n y t o i n . Table 1 outlines a c o m p a r i s o n of p h e n y t o i n a n d fosphenytoin. N u r s i n g care a n d m o n i t o r i n g Of t h e p a t i e n t r e c e i v i n g IV f o s p h e n y t o i n is u n c h a n g e d from t h a t of p a r e n t e r a l p h e n y t o i n . C o n t i n u o u s cardiac m o n i t o r i n g is r e c o m m e n d e d d u r i n g IV infusion of p h e n y t o i n or f o s p h e n y t o i n . However, p a t i e n t s c a n b e g i v e n both l o a d i n g a n d m a i n t e n a n c e doses of IM fosphenytoin, w h i c h does n o t r e q u i r e cardiac monitoring. N u r s i n g t i m e is d e c r e a s e d b e c a u s e of t h e shorter p r e p a r a t i o n time, shorter i n f u s i o n time, a n d the i n f r e q u e n c y of a d v e r s e d r u g reactions. Initiation of oral p h e n y t o i n r e m a i n s u n c h a n g e d o n c e the p a t i e n t ' s c o n d i t i o n has stabilized. Clinical trials for f o s p h e n y t o i n u s e h a v e n o t b e e n c o n d u c t e d for children y o u n g e r t h a n 5 years of age; therefore f o s p h e n y t o i n does n o t have a n a p p r o v e d i n d i c a t i o n i n this group. 1
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Volume 22, Number 5
F o s p h e n y t o i n is more e x p e n s i v e t h a n p h e n y t o i n . P h e n y t o i n costs a p p r o x i m a t e l y $2 to $3 for a n average l o a d i n g dose, w h e r e a s fosphenytoin, currently b e i n g priced, is e x p e c t e d to cost in the r a n g e of $60 to $100 for a n a v e r a g e l o a d i n g dose. However, d e c r e a s e d p r e p a r a t i o n time, d e c r e a s e d complications, i m p r o v e d compatibility, a n d equal efficacy m a k e f o s p h e n y t o i n a feasible alternative to s t a n d a r d parenteral p h e n y t o i n . References
1. Wilder BJ, editor. Advances in anticonvulsants: new directions in acute seizure therapy [seminar]. Gainesville (FL): Southern Clinical Neurological Society, 1995. 2. Lehne R. Pharmacology for nursing care. Philadelphia: WB Saunders, 1994:233. 3. Bebin M, Bleck T. New anticonvulsant drugs. Drugs 1994;48:157-60. 4. Parke-Davis. Cerebyx: Package insert [draft]. Morris Plains (NJ): The Manufacturer, 1996. 5. Physicians' desk reference. Monvale (NJ): Medical Economics Data Production, 1995.
Contributions to this column may be sent to J a n e t H i cks Keen, RN, MS, CCRN, CEN, 9090 OM Southwick Pass, Alpharetta, GA 30202; phone (770) 343-9512.
A
Dosing and administration F o s p h e n y t o i n is biologically b i o e q u i v a l e n t to p h e n y toin; t h e r e f o r e t h e e f f i c a c y r e m a i n s t h e s a m e . F o s p h e n y t o i n d o s i n g is also e q u i v a l e n t to t h a t of p h e n y t o i n . A s t a n d a r d l o a d i n g d o s e of f o s p h e n y t o i n is 15 to 20 m g / k g , or a b o u t 1200 to 1600 m g for a n 80 Kathleen Bradbury-Golas is a clinical nurse specialist, Critical Care and Medical-Surgical Department, Somers Point, New Jersey. Linda Carson is a staff nurse, Emergency Department, Shore Memorial Hospital, Somers Point, New Jersey. For reprints, write Kathleen Bradbury-Golas, RN, MSN, CNS, C, CCRN, 14 Avalon Woods Court, Swainton, NJ 08210. J Emerg Nurs 1996;22:431-2. Copyright 9 1996 by the Emergency Nurses Association. 0099-1767/96 $5.00 + 0 18/62/76730
k g individual, F o s p h e n y t o i n c a n b e i n f u s e d at a m a x i m u m r a t e of 150 m g / m i n . This m e a n s t h a t a n initial d o s e c a n b e g i v e n over a p p r o x i m a t e l y 8 to 10 minu t e s ( b a s e d on an 80 k g person) c o m p a r e d w i t h t h e 20 to 30 m i n u t e s t y p i c a l l y r e q u i r e d for a s t a n d a r d d o s e of p h e n y t o i n . 1
In addition, f o s p h e n y t o i n c a n be a d m i n i s t e r e d intramuscularly.
In addition, f o s p h e n y t o i n c a n b e a d m i n i s t e r e d i n t r a m u s c u l a r l y if IV a c c e s s is n o t o b t a i n e d or if a t e m p o r a r y s u b s t i t u t e for oral p h e n y t o i n is required. In controlled trials, f o s p h e n y t o i n w a s a d m i n i s t e r e d i n t r a m u s c u l a r l y a s a s i n g l e daily dose, w i t h either one or t w o injection sites. T h e m a n u f a c t u r e r reports t h a t i n j e c t i o n s of 5 to 20 ml at a s i n g l e s i t e w e r e well t o l e r a t e d b y t h e p a t i e n t s p a r t i c i p a t i n g in t h e s e trials. 4 I n t r a m u s c u l a r i n j e c t i o n is n o t r e c o m m e n d e d with phenytoin. 5 F o s p h e n y t o i n is s u p p l i e d in 2 mI (150 mg) a n d 10 ml (750 mg) vials a n d m u s t b e refrigerated until used. If a d m i x e d in a d v a n c e , f o s p h e n y t o i n is stable for 8 hours at room t e m p e r a t u r e or 24 hours if refrigerated. 1 F o s p h e n y t o i n can b e m i x e d for injection to a c o n c e n tration r a n g i n g from 2.5 to 20 mg/ml. For example, it c a n b e m i x e d in 50 to 400 ml of 5% d e x t r o s e in w a t e r or normal saline solution d e p e n d i n g on t h e n e e d e d concentration. Filtering is n o t r e q u i r e d as w i t h p h e n y toin. P h e n y t o i n is s t a b l e at room t e m p e r a t u r e w h e n n o t mixed; however, it c a n n o t b e p r e m i x e d b e c a u s e of its lack of solubility a n d resultant precipitation. Standard laboratory chromatographic assays u s e d to m e a s u r e p h e n y t o i n also are u s e d to a s c e r t a i n t h e r a p e u t i c levels of f o s p h e n y t o i n . However, a 2- to 4-hour w a i t i n g p e r i o d is r e c o m m e n d e d after fosp h e n y t o i n infusion for g r e a t e s t a c c u r a c y .
October 1996 431
JOURNAL OF EMERGENCYNURSING/Bradbury-Golasand Carson
Table 1 Comparison of phenytoin and fosphenytoin 1"~ Phenytoin
Propylene glycol/ethanol base pH of 12 Compatible with NSS only; precipitation can occur IV filter required IM injection not recommended Maximum IV rate of 50 mg/min Cardiac monitoring required Side effects Pain and burning at IV infusion site Vein irritation Potential necrosis Hypotension Dysrhythmias Potential cardiac arrest Stability Unmixed: Stable at room temperature Premixed: Unable to premix because of rapid precipitation Therapeutic levels: Wait 1 to 2 hours before obtaining blood specimen
Fosphenytoin
No propylene glycol/ethanol base; water-soluble pH 8.5 to 8.8 Compatible with common IV solutions; no precipitation No filter required Well absorbed IM IV rate of 150 mg/min Cardiac monitoring required (IV only) Side effects Minimal infusion complications Paresthesia Pruritis Infrequent hypotension Infrequent dysrhythmias Infrequent cardiac arrests Stability Unmixed: Stable without refrigeration for 48 hours Premixed: Stable with refrigeration for 24 hours Therapeutic levels: Wait 2 to 4 hours before obtaining blood specimen
NSS, Normal saline solution; IM, intramuscular.
S i d e effects
Side effects of f o s p h e n y t o i n are similar to those of p h e n y t o i n b u t far less frequent. There also m a y b e t r a n s i e n t p a r e s t h e s i a a n d pruritis, primarily in t h e p e r i n e a l area, w h i c h usually resolves s p o n t a n e o u s l y after c o m p l e t i o n of t h e infusion. The i n t e n s i t y of the p a r e s t h e s i a a n d pruritis is rate related. With IV a d m i n i s t r a t i o n t h e rate c a n b e d e c r e a s e d to r e d u c e t h e effects. More s e r i o u s side effects i n c l u d i n g h y p o t e n s i o n , d y s r h y t h m i a s , a n d cardiac arrest have b e e n reported. However, the i n c i d e n c e of t h e s e side effects is lower for f o s p h e n y t o i n t h a n w i t h p h e n y t o i n . Table 1 outlines a c o m p a r i s o n of p h e n y t o i n a n d fosphenytoin. N u r s i n g care a n d m o n i t o r i n g Of t h e p a t i e n t r e c e i v i n g IV f o s p h e n y t o i n is u n c h a n g e d from t h a t of p a r e n t e r a l p h e n y t o i n . C o n t i n u o u s cardiac m o n i t o r i n g is r e c o m m e n d e d d u r i n g IV infusion of p h e n y t o i n or f o s p h e n y t o i n . However, p a t i e n t s c a n b e g i v e n both l o a d i n g a n d m a i n t e n a n c e doses of IM fosphenytoin, w h i c h does n o t r e q u i r e cardiac monitoring. N u r s i n g t i m e is d e c r e a s e d b e c a u s e of t h e shorter p r e p a r a t i o n time, shorter i n f u s i o n time, a n d the i n f r e q u e n c y of a d v e r s e d r u g reactions. Initiation of oral p h e n y t o i n r e m a i n s u n c h a n g e d o n c e the p a t i e n t ' s c o n d i t i o n has stabilized. Clinical trials for f o s p h e n y t o i n u s e h a v e n o t b e e n c o n d u c t e d for children y o u n g e r t h a n 5 years of age; therefore f o s p h e n y t o i n does n o t have a n a p p r o v e d i n d i c a t i o n i n this group. 1
432
Volume 22, Number 5
F o s p h e n y t o i n is more e x p e n s i v e t h a n p h e n y t o i n . P h e n y t o i n costs a p p r o x i m a t e l y $2 to $3 for a n average l o a d i n g dose, w h e r e a s fosphenytoin, currently b e i n g priced, is e x p e c t e d to cost in the r a n g e of $60 to $100 for a n a v e r a g e l o a d i n g dose. However, d e c r e a s e d p r e p a r a t i o n time, d e c r e a s e d complications, i m p r o v e d compatibility, a n d equal efficacy m a k e f o s p h e n y t o i n a feasible alternative to s t a n d a r d parenteral p h e n y t o i n . References
1. Wilder BJ, editor. Advances in anticonvulsants: new directions in acute seizure therapy [seminar]. Gainesville (FL): Southern Clinical Neurological Society, 1995. 2. Lehne R. Pharmacology for nursing care. Philadelphia: WB Saunders, 1994:233. 3. Bebin M, Bleck T. New anticonvulsant drugs. Drugs 1994;48:157-60. 4. Parke-Davis. Cerebyx: Package insert [draft]. Morris Plains (NJ): The Manufacturer, 1996. 5. Physicians' desk reference. Monvale (NJ): Medical Economics Data Production, 1995.
Contributions to this column may be sent to J a n e t H i cks Keen, RN, MS, CCRN, CEN, 9090 OM Southwick Pass, Alpharetta, GA 30202; phone (770) 343-9512.