Oral diazepam (Valium), given at times of fever, safely reduces the risk of febrile seizure recurrence in infants and children, according to a study published in the July 8 issue of the New England Journal of Medicine * and funded by the National Institute of Neurological Disorders and Stroke (NINDS). Febrile seizures are fever-triggered convulsions that occur in approximately 3-4 percent of all children in the United States.
Diazepam is a benzodiazepine. It works by slowing down the movement of chemicals in the brain. This results in a reduction in nervous tension (anxiety) and muscle spasm, and also causes sedation.
Thursday, February 12, 2009
ANTIEPILEPTIC MEDICATIONS
CARBAMAZEPINE
Mechanism of Action :
Carbamazepine reduces polysynaptic responses and blocks post-tetanic potentiation. It is effective in partial and generalised convulsions as well as in mixed types but not in petit mal seizures. It reduces or abolishes pain in trigeminal and glossopharyngeal neuralgia.
Indication, Dosage and Frequency :
Oral
EPILEPSY
Adult: Initially, 100-200 mg once or bid gradually increased by increments of 100-200 mg every 2 wk. Maintenance: 0.8-1.2 g daily in divided doses. Max dose: 2 g daily.
Child: ≤1 yr: 100-200 mg daily, 1-5 yr: 200-400 mg daily, 5-10 yr: 400-600 mg daily, 10-15 yr: 0.6-1 g daily. Alternatively, 10-20 mg/kg daily in divided doses.
TRIGEMINAL NEURALGIA
Adult: Initially, 100 mg once or bid gradually increased as necessary. Maintenance: 400-800 mg daily in 2-4 divided doses. Max: 1.2 g daily.
PROPHYLAXIS OF BIPOLAR DISORDER
Adult: Initially, 400 mg daily in divided doses gradually increased if necessary. Maintenance: 400-600 mg daily. Max: 1.6 g daily.
Rectal
EPILEPSY
Adult: 250 mg every 6 hr for patients incapable of oral treatment
Interactions :
Reduces tolerance to alcohol; shortens T½ of doxycycline. Decreased efficacy of oral contraceptives when used with carbamazepine. Increased plasma concentrations of carbamazepine by propoxyphene. Serum level decreases with phenytoin, phenobarbital, primidone
Mechanism of Action :
Carbamazepine reduces polysynaptic responses and blocks post-tetanic potentiation. It is effective in partial and generalised convulsions as well as in mixed types but not in petit mal seizures. It reduces or abolishes pain in trigeminal and glossopharyngeal neuralgia.
Indication, Dosage and Frequency :
Oral
EPILEPSY
Adult: Initially, 100-200 mg once or bid gradually increased by increments of 100-200 mg every 2 wk. Maintenance: 0.8-1.2 g daily in divided doses. Max dose: 2 g daily.
Child: ≤1 yr: 100-200 mg daily, 1-5 yr: 200-400 mg daily, 5-10 yr: 400-600 mg daily, 10-15 yr: 0.6-1 g daily. Alternatively, 10-20 mg/kg daily in divided doses.
TRIGEMINAL NEURALGIA
Adult: Initially, 100 mg once or bid gradually increased as necessary. Maintenance: 400-800 mg daily in 2-4 divided doses. Max: 1.2 g daily.
PROPHYLAXIS OF BIPOLAR DISORDER
Adult: Initially, 400 mg daily in divided doses gradually increased if necessary. Maintenance: 400-600 mg daily. Max: 1.6 g daily.
Rectal
EPILEPSY
Adult: 250 mg every 6 hr for patients incapable of oral treatment
Interactions :
Reduces tolerance to alcohol; shortens T½ of doxycycline. Decreased efficacy of oral contraceptives when used with carbamazepine. Increased plasma concentrations of carbamazepine by propoxyphene. Serum level decreases with phenytoin, phenobarbital, primidone
CLONAZEPAM
Mechanism of Action :
Clonazepam is an effective anticonvulsant. It raises the threshold for propagation of seizure activity and prevents generalisation of focal or local activity. Clinically, it improves focal epilepsy and generalised seizures. It is also believed to enhance the activity of GABA, and acts as anxiolytic.
Indication, Dosage and Frequency :
Oral
EPILEPSY
Adult: Initially, 1 mg given at night for 4 nights, gradually increased over 2-4 wk. Maintenance: 4-8 mg daily. Max: 20 mg/day
Child: 1-5 yr: 250 mcg daily; 5-12 yr: 500 mcg daily. Maintenance (given in 2-4 divided doses): Infants: 0.5-1 mg daily; 1-5 yr: 1-3 mg daily; 5-12 yr: 3-6 mg daily. Max: 200 mcg/kg/day
Elderly: Initially, 500 mcg at night for 4 nights, may gradually increase over 2-4 wk.
PANIC DISORDER
Adult: Initially, 250 mcg bid, increased after 3 days up to 1 mg daily. Max: 4 mg daily.
Intravenous
EMERGENCY MANAGEMENT OF STATUS EPILEPTICUS
Adult: 1 mg as inj or infusion given over at least 2 min, repeated if necessary.
Child: and infants: 500 mcg as inj or infusion given over at least 2 min, repeated if necessary
Interactions :
Carbamazepine, phenobarbitone or phenytoin may accelerate clonazepam metabolism.
Clonazepam is an effective anticonvulsant. It raises the threshold for propagation of seizure activity and prevents generalisation of focal or local activity. Clinically, it improves focal epilepsy and generalised seizures. It is also believed to enhance the activity of GABA, and acts as anxiolytic.
Indication, Dosage and Frequency :
Oral
EPILEPSY
Adult: Initially, 1 mg given at night for 4 nights, gradually increased over 2-4 wk. Maintenance: 4-8 mg daily. Max: 20 mg/day
Child: 1-5 yr: 250 mcg daily; 5-12 yr: 500 mcg daily. Maintenance (given in 2-4 divided doses): Infants: 0.5-1 mg daily; 1-5 yr: 1-3 mg daily; 5-12 yr: 3-6 mg daily. Max: 200 mcg/kg/day
Elderly: Initially, 500 mcg at night for 4 nights, may gradually increase over 2-4 wk.
PANIC DISORDER
Adult: Initially, 250 mcg bid, increased after 3 days up to 1 mg daily. Max: 4 mg daily.
Intravenous
EMERGENCY MANAGEMENT OF STATUS EPILEPTICUS
Adult: 1 mg as inj or infusion given over at least 2 min, repeated if necessary.
Child: and infants: 500 mcg as inj or infusion given over at least 2 min, repeated if necessary
Interactions :
Carbamazepine, phenobarbitone or phenytoin may accelerate clonazepam metabolism.
CLORAZEPATE
Mechanism of Action :
Clorazepate binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron within the central nervous system, limbic system, reticular formation resulting to an increase in chloride ion permeability which further leads to hyperpolarisation and stabilisation.
Onset: 1-2 hrs.
Duration: 8-24 hrs.
Indication, Dosage and Frequency
Oral
ANXIETY
Adult: 7.5 mg tid.
Elderly: and debilitated patients: Initiate at lower dose and adjust slowly.
ALCOHOL WITHDRAWAL SYNDROME
Adult: 90 mg daily in divided doses.
Child: 9-12 yr old: 60 mg in divided doses.
Elderly: and debilitated patients: Initiate at lower dose and adjust slowly.
EPILEPSY
Adult: 90 mg daily in divided doses.
Child: 9-12 yr old: 60 mg in divided doses.
Elderly: and debilitated patients: Initiate at lower dose and adjust slowly.
Interactions :
Potentiates CNS effects of narcotic analgesics, barbiturates, phenothiazines, ethanol, antihistamines, MAO Inhibitors, sedative-hypnotics, cyclic antidepressants. CYP3A4 inhibitors eg, amprenavir, cimetidine, ciprofloxacin, clarithromycin may increase serum conc and toxicity of clorazepate. Carbamazepine, rifampin and rifabutin may decrease clorazepate therapeutic effects by enhancement of clorazepate metabolism.
Grapefruit juice increases serum conc or toxicity risk of clorazepate. Herbs or nutraceuticals eg, valerian, St. John's wort, kava kava and gotu kola may increase CNS depression upon concomitant admin with clorazepate.
Clorazepate binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron within the central nervous system, limbic system, reticular formation resulting to an increase in chloride ion permeability which further leads to hyperpolarisation and stabilisation.
Onset: 1-2 hrs.
Duration: 8-24 hrs.
Indication, Dosage and Frequency
Oral
ANXIETY
Adult: 7.5 mg tid.
Elderly: and debilitated patients: Initiate at lower dose and adjust slowly.
ALCOHOL WITHDRAWAL SYNDROME
Adult: 90 mg daily in divided doses.
Child: 9-12 yr old: 60 mg in divided doses.
Elderly: and debilitated patients: Initiate at lower dose and adjust slowly.
EPILEPSY
Adult: 90 mg daily in divided doses.
Child: 9-12 yr old: 60 mg in divided doses.
Elderly: and debilitated patients: Initiate at lower dose and adjust slowly.
Interactions :
Potentiates CNS effects of narcotic analgesics, barbiturates, phenothiazines, ethanol, antihistamines, MAO Inhibitors, sedative-hypnotics, cyclic antidepressants. CYP3A4 inhibitors eg, amprenavir, cimetidine, ciprofloxacin, clarithromycin may increase serum conc and toxicity of clorazepate. Carbamazepine, rifampin and rifabutin may decrease clorazepate therapeutic effects by enhancement of clorazepate metabolism.
Grapefruit juice increases serum conc or toxicity risk of clorazepate. Herbs or nutraceuticals eg, valerian, St. John's wort, kava kava and gotu kola may increase CNS depression upon concomitant admin with clorazepate.
DIAZEPAM
Mechanism of Action :
Diazepam is a long-acting benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant and amnestic properties. It increases neuronal membrane permeability to chloride ions by binding to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron within the CNS and enhancing the GABA inhibitory effects resulting in hyperpolarisation and stabilisation.
Indication, Dosage and Frequency :
Oral
SHORT-TERM MANAGEMENT OF ANXIETY
Adult: 2 mg tid. Max: 30 mg daily.
Elderly: Dose reduction may be required.
INSOMNIA ASSOCIATED WITH ANXIETY
Adult: 5-15 mg at bedtime.
Elderly: Dose reduction may be required.
SLEEPWALKING
Child: and adolescents (up to 18 yr): 1-5 mg at bedtime.
Elderly: Dose reduction may be required.
NIGHT TERRORS
Child: and adolescents (up to 18 yr): 1-5 mg at bedtime.
Elderly: Dose reduction may be required.
ANAESTHETIC PREMEDICATION
Adult: 5-15 mg given before general anaesthesia.
Child: 1-12 mth: 250 mcg/kg; 1-5 yr: 2.5 mg; 5-12 yr: 5 mg.
Elderly: Dose reduction may be required.
ADJUNCT IN THE MANAGEMENT OF SEIZURES
Adult: 2-60 mg daily in divided doses.
Elderly: Dose reduction may be required.
MUSCLE SPASMS
Adult: 2-15 mg daily in divided doses, increased up to 60 mg daily in severe spastic disorders e.g. cerebral palsy. Max: 60 mg/day.
Child: 1-12 mth: 250 mcg/kg; 1-5 yr: 2.5 mg; 5-12 year: 5 mg; 12-18 yr: 10 mg. Max: 40 mg/day.
Elderly: Dose reduction may be required.
ACUTE SYMPTOMS OF ALCOHOL WITHDRAWAL
Adult: 5-20 mg repeated after 2-4 hr if necessary. Alternatively, 10 mg 3-4 times daily on the 1st day reduced to 5 mg 3-4 times daily as required.
Elderly: Dose reduction may be required.
Intravenous
ANAESTHETIC PREMEDICATION
Adult: 100-200 mcg/kg.
Child: >1 mth: 100-200 mcg/kg. Max: 1 mth-12 yr: 5 mg/day; 12-18 yr: 20 mg/day.
Elderly: Dose reduction may be required.
MUSCLE SPASM ASSOCIATED WITH TETANUS
Adult: 100-300 mcg/kg given every 1-4 hr by IV inj. Alternatively, 3-10 mg/kg is given over 24 hr by continuous IV infusion or by nasoduodenal tube using a suitable liquid oral dose preparation.
Child: >1 mth: 100-300 mcg/kg given every 1-4 hr by IV inj. Alternatively, 3-10 mg/kg is given over 24 hr by continuous IV infusion or by nasoduodenal tube using a suitable liquid oral dose preparation.
Elderly: Dose reduction may be required.
Interactions :
Increased clearance of diazepam when used with phenytoin, carbamazepine and phenobarbital. Reversible deterioration of parkinsonism may occur when given together with levodopa. Combination with lithium may produce hypothermia.
Grape juice may increase serum levels and toxicity.
Diazepam is a long-acting benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant and amnestic properties. It increases neuronal membrane permeability to chloride ions by binding to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron within the CNS and enhancing the GABA inhibitory effects resulting in hyperpolarisation and stabilisation.
Indication, Dosage and Frequency :
Oral
SHORT-TERM MANAGEMENT OF ANXIETY
Adult: 2 mg tid. Max: 30 mg daily.
Elderly: Dose reduction may be required.
INSOMNIA ASSOCIATED WITH ANXIETY
Adult: 5-15 mg at bedtime.
Elderly: Dose reduction may be required.
SLEEPWALKING
Child: and adolescents (up to 18 yr): 1-5 mg at bedtime.
Elderly: Dose reduction may be required.
NIGHT TERRORS
Child: and adolescents (up to 18 yr): 1-5 mg at bedtime.
Elderly: Dose reduction may be required.
ANAESTHETIC PREMEDICATION
Adult: 5-15 mg given before general anaesthesia.
Child: 1-12 mth: 250 mcg/kg; 1-5 yr: 2.5 mg; 5-12 yr: 5 mg.
Elderly: Dose reduction may be required.
ADJUNCT IN THE MANAGEMENT OF SEIZURES
Adult: 2-60 mg daily in divided doses.
Elderly: Dose reduction may be required.
MUSCLE SPASMS
Adult: 2-15 mg daily in divided doses, increased up to 60 mg daily in severe spastic disorders e.g. cerebral palsy. Max: 60 mg/day.
Child: 1-12 mth: 250 mcg/kg; 1-5 yr: 2.5 mg; 5-12 year: 5 mg; 12-18 yr: 10 mg. Max: 40 mg/day.
Elderly: Dose reduction may be required.
ACUTE SYMPTOMS OF ALCOHOL WITHDRAWAL
Adult: 5-20 mg repeated after 2-4 hr if necessary. Alternatively, 10 mg 3-4 times daily on the 1st day reduced to 5 mg 3-4 times daily as required.
Elderly: Dose reduction may be required.
Intravenous
ANAESTHETIC PREMEDICATION
Adult: 100-200 mcg/kg.
Child: >1 mth: 100-200 mcg/kg. Max: 1 mth-12 yr: 5 mg/day; 12-18 yr: 20 mg/day.
Elderly: Dose reduction may be required.
MUSCLE SPASM ASSOCIATED WITH TETANUS
Adult: 100-300 mcg/kg given every 1-4 hr by IV inj. Alternatively, 3-10 mg/kg is given over 24 hr by continuous IV infusion or by nasoduodenal tube using a suitable liquid oral dose preparation.
Child: >1 mth: 100-300 mcg/kg given every 1-4 hr by IV inj. Alternatively, 3-10 mg/kg is given over 24 hr by continuous IV infusion or by nasoduodenal tube using a suitable liquid oral dose preparation.
Elderly: Dose reduction may be required.
Interactions :
Increased clearance of diazepam when used with phenytoin, carbamazepine and phenobarbital. Reversible deterioration of parkinsonism may occur when given together with levodopa. Combination with lithium may produce hypothermia.
Grape juice may increase serum levels and toxicity.
ETHOSUXIMIDE
Mechanism of Action :
Ethosuximide is used mainly in the management of absence (petite mal) seizures. It is usually ineffective in the management of partial seizures with complex symptomatology or tonic-clonic seizures.
Indication, Dosage and Frequency :
Oral
ABSENCE SEIZURES
Adult: Initially, 500 mg daily, may increase in steps of 250 mg at intervals of 4-7 days. Usual dose: 1-1.5 g daily. Optimum plasma concentration: 40-100 mg/L (300-700 micromol/L). Max: Up to 2 g in some patients. Strict supervision is recommended if dose >1.5 g daily.
Child: <6 yr: Initially, 250 mg daily, may increase gradually to usual dose of 20 mg/kg daily. ≥6 yr: Initially, 500 mg daily, may increase in steps of 250 mg at intervals of 4-7 days. Usual dose: 1-1.5 g daily. Max: <6 yr: Up to 1 g/day and ≥6 yr: 2 g/day .
Interactions :
Isoniazid may increase the serum concentration of ethosuximide, leading to toxicity. Antipsychotics, antidepressants, MAOIs, and mefloquine may antagonise anticonvulsant effects of ethosuximide. Plasma conc of ethosuximide may be reduced by carbamazepine, phenobarbital, phenytoin, and primidone; and affected by valproate. Chloroquine or hydroxychloroquine may increase risk of convulsions.
Ethosuximide is used mainly in the management of absence (petite mal) seizures. It is usually ineffective in the management of partial seizures with complex symptomatology or tonic-clonic seizures.
Indication, Dosage and Frequency :
Oral
ABSENCE SEIZURES
Adult: Initially, 500 mg daily, may increase in steps of 250 mg at intervals of 4-7 days. Usual dose: 1-1.5 g daily. Optimum plasma concentration: 40-100 mg/L (300-700 micromol/L). Max: Up to 2 g in some patients. Strict supervision is recommended if dose >1.5 g daily.
Child: <6 yr: Initially, 250 mg daily, may increase gradually to usual dose of 20 mg/kg daily. ≥6 yr: Initially, 500 mg daily, may increase in steps of 250 mg at intervals of 4-7 days. Usual dose: 1-1.5 g daily. Max: <6 yr: Up to 1 g/day and ≥6 yr: 2 g/day .
Interactions :
Isoniazid may increase the serum concentration of ethosuximide, leading to toxicity. Antipsychotics, antidepressants, MAOIs, and mefloquine may antagonise anticonvulsant effects of ethosuximide. Plasma conc of ethosuximide may be reduced by carbamazepine, phenobarbital, phenytoin, and primidone; and affected by valproate. Chloroquine or hydroxychloroquine may increase risk of convulsions.
GABAPENTIN
Mechanism of Action :
Gabapentin is structurally related to the neurotransmitter GABA but is neither a GABA agonist nor antagonist. Gabapentin-binding sites have been identified throughout the brain tissues e.g. neocortex and hippocampus. However, the exact mechanism of action is still unknown.
Oral
EPILEPSY (PARTIAL SEIZURES WITH OR WITHOUT SECONDARY GENERALISATION)
Adult: Initially, 300 mg on the 1st day, 300 mg bid on the 2nd day and 300 mg tid on the 3rd day. Thereafter, may increase dose until effective antiepileptic control is achieved. Usual maintenance range: 0.9-3.6 g daily; daily dose to be taken in 3 equally divided doses and max dosing interval: 12 hr. Max: 4.8 g daily.
Child: 6-12 yr: Initially, 10 mg/kg on the 1st day, 20 mg/kg on the 2nd day and 25-35 mg/kg on the 3rd day. Maintenance: 1200 mg daily (37-50 kg); 900 mg daily (26-36 kg). Total daily dose to be taken in 3 equally divided doses.
NEUROPATHIC PAIN
Adult: Titrate to a max of 1.8 g daily in 3 divided doses.
Interactions :
Cimetidine may reduce gabapentin clearance. Absorption reduced with antacids.
Gabapentin is structurally related to the neurotransmitter GABA but is neither a GABA agonist nor antagonist. Gabapentin-binding sites have been identified throughout the brain tissues e.g. neocortex and hippocampus. However, the exact mechanism of action is still unknown.
Oral
EPILEPSY (PARTIAL SEIZURES WITH OR WITHOUT SECONDARY GENERALISATION)
Adult: Initially, 300 mg on the 1st day, 300 mg bid on the 2nd day and 300 mg tid on the 3rd day. Thereafter, may increase dose until effective antiepileptic control is achieved. Usual maintenance range: 0.9-3.6 g daily; daily dose to be taken in 3 equally divided doses and max dosing interval: 12 hr. Max: 4.8 g daily.
Child: 6-12 yr: Initially, 10 mg/kg on the 1st day, 20 mg/kg on the 2nd day and 25-35 mg/kg on the 3rd day. Maintenance: 1200 mg daily (37-50 kg); 900 mg daily (26-36 kg). Total daily dose to be taken in 3 equally divided doses.
NEUROPATHIC PAIN
Adult: Titrate to a max of 1.8 g daily in 3 divided doses.
Interactions :
Cimetidine may reduce gabapentin clearance. Absorption reduced with antacids.
LAMOTRIGINE
Mechanism of Action :
Lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilising neuronal membranes and consequently inhibiting pathological release of excitatory amino acids (e.g. glutamate and aspartate). These amino acids play a role in the generation and spread of epileptic seizures.
Indication, Dosage and Frequency :
Oral
MONOTHERAPY IN EPILEPSY
Adult: Initially, 25 mg once daily for 2 wk followed by 50 mg once daily for 2 wk; thereafter, increase the dose by a max of 50-100 mg every 1-2 wk to usual maintenance doses of 100-200 mg daily, as a single dose or in 2 divided doses. Some patients may require up to 500 mg daily.
Child: >12 yr: Initially, 25 mg once daily for 2 wk followed by 50 mg once daily for 2 wk; thereafter, increase the dose by a max of 50-100 mg every 1-2 wk to usual maintenance doses of 100 -200 mg daily, as a single dose or in 2 divided doses. Some patients may require up to 500 mg daily. <12 yr: Not recommended.
Max Dosage: Adult: 500 mg daily.
ADJUNCT IN EPILEPSY
Adult: With valproate: Initially, 25 mg on alternate days for 2 wk followed by 25 mg once daily for 2 wk; thereafter, increase by a max of 25-50 mg every 1-2 wk; usual maintenance doses: 100-200 mg daily in 1-2 divided doses. With enzyme-inducing antiepileptics but not with valproate: 50 mg once daily for 2 wk followed by 50 mg bid for 2 wk; thereafter, increase by a max of 100 mg every 1-2 wk; usual maintenance doses: 200-400 mg/day in 2 divided doses; up to 700 mg/day in some patients. With oxcarbazepine but no enzyme-inducing or -inhibiting antiepileptics: 25 mg once daily for 2 wk followed by 50 mg once daily for 2 wk; thereafter increase dose by a max of 50-100 mg every 1-2 wk; usual maintenance doses: 100-200 mg daily in 1-2 divided doses; up to 500 mg daily in some patients.
Child: With valproate: Initially, 0.15 mg/kg once daily for 2 wk followed by 0.3 mg/kg once daily for 2 wk; thereafter, increase by a max of 0.3 mg/kg every 1-2 wk to usual maintenance doses of 1-5 mg/kg once daily or in 2 divided doses.
BIPOLAR DISORDER
Adult: Monotherapy: Initially, 25 mg once daily for 2 wk followed by 50 mg once daily for 2 wk; thereafter, double the daily dose at wkly intervals to usual maintenance dose of 200 mg daily. Max dose: 200 mg/day. With valproate: Initially, 25 mg every other day for 2 wk followed by 25 mg once daily for 2 wk; thereafter, double the daily dose at wkly intervals to usual maintenance dose of 100 mg daily. With enzyme-inducing antiepileptics but not with valproate: Initially, 50 mg once daily for 2 wk followed by 100 mg daily in 2 divided doses for 2 wk; thereafter, increase in 100-mg increments wkly to usual maintenance dose of 400 mg daily in 2 divided doses.
Interactions :
Metabolism enhanced by enzyme-inducing drugs e.g. phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, ethinyloestradiol/levonorgestrel combination. Metabolism reduced by sodium valproate.
Lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilising neuronal membranes and consequently inhibiting pathological release of excitatory amino acids (e.g. glutamate and aspartate). These amino acids play a role in the generation and spread of epileptic seizures.
Indication, Dosage and Frequency :
Oral
MONOTHERAPY IN EPILEPSY
Adult: Initially, 25 mg once daily for 2 wk followed by 50 mg once daily for 2 wk; thereafter, increase the dose by a max of 50-100 mg every 1-2 wk to usual maintenance doses of 100-200 mg daily, as a single dose or in 2 divided doses. Some patients may require up to 500 mg daily.
Child: >12 yr: Initially, 25 mg once daily for 2 wk followed by 50 mg once daily for 2 wk; thereafter, increase the dose by a max of 50-100 mg every 1-2 wk to usual maintenance doses of 100 -200 mg daily, as a single dose or in 2 divided doses. Some patients may require up to 500 mg daily. <12 yr: Not recommended.
Max Dosage: Adult: 500 mg daily.
ADJUNCT IN EPILEPSY
Adult: With valproate: Initially, 25 mg on alternate days for 2 wk followed by 25 mg once daily for 2 wk; thereafter, increase by a max of 25-50 mg every 1-2 wk; usual maintenance doses: 100-200 mg daily in 1-2 divided doses. With enzyme-inducing antiepileptics but not with valproate: 50 mg once daily for 2 wk followed by 50 mg bid for 2 wk; thereafter, increase by a max of 100 mg every 1-2 wk; usual maintenance doses: 200-400 mg/day in 2 divided doses; up to 700 mg/day in some patients. With oxcarbazepine but no enzyme-inducing or -inhibiting antiepileptics: 25 mg once daily for 2 wk followed by 50 mg once daily for 2 wk; thereafter increase dose by a max of 50-100 mg every 1-2 wk; usual maintenance doses: 100-200 mg daily in 1-2 divided doses; up to 500 mg daily in some patients.
Child: With valproate: Initially, 0.15 mg/kg once daily for 2 wk followed by 0.3 mg/kg once daily for 2 wk; thereafter, increase by a max of 0.3 mg/kg every 1-2 wk to usual maintenance doses of 1-5 mg/kg once daily or in 2 divided doses.
BIPOLAR DISORDER
Adult: Monotherapy: Initially, 25 mg once daily for 2 wk followed by 50 mg once daily for 2 wk; thereafter, double the daily dose at wkly intervals to usual maintenance dose of 200 mg daily. Max dose: 200 mg/day. With valproate: Initially, 25 mg every other day for 2 wk followed by 25 mg once daily for 2 wk; thereafter, double the daily dose at wkly intervals to usual maintenance dose of 100 mg daily. With enzyme-inducing antiepileptics but not with valproate: Initially, 50 mg once daily for 2 wk followed by 100 mg daily in 2 divided doses for 2 wk; thereafter, increase in 100-mg increments wkly to usual maintenance dose of 400 mg daily in 2 divided doses.
Interactions :
Metabolism enhanced by enzyme-inducing drugs e.g. phenytoin, carbamazepine, phenobarbitone, primidone, rifampicin, ethinyloestradiol/levonorgestrel combination. Metabolism reduced by sodium valproate.
PHENOBARBITAL
Mechanism of Action :
Phenobarbitone is a short-acting barbiturate. It depresses the sensory cortex, reduces motor activity, changes cerebellar function, and produces drowsiness, sedation and hypnosis. Its anticonvulsant property is exhibited at high doses.
Onset: Hypnosis: Oral: 20-60 min; IV: Approx 5 min.
Duration: Oral: 6-10 hr; IV: 4-10 hr.
Indication, Dosage and Frequency :
Oral
PARTIAL SEIZURES
Adult: 60-180 mg daily taken at night. Titrate dose according to patient's needs to achieve adequate control of seizures. Plasma concentrations of 15-40 mcg/ml (65-170 micromol/l) are usually required.
Child: 1 mth-12 yr: Initially, 1-1.5 mg/kg bid. Increase by 2 mg/kg daily, as required, to a maintenance dose of 2.5-4 mg/kg once or bid. 12-18 yr: Initially, 60-180 mg bid. Maintenance: 60-180 mg once daily.
GENERALISED TONIC-CLONIC SEIZURES
Adult: 60-180 mg daily taken at night. Titrate dose according to patient's needs to achieve adequate control of seizures. Plasma concentrations of 15-40 mcg/ml (65-170 micromol/l) are usually required.
Child: 1 mth-12 yr: Initially, 1-1.5 mg/kg bid. Increase by 2 mg/kg daily, as required, to a maintenance dose of 2.5-4 mg/kg once or bid. 12-18 yr: Initially, 60-180 mg bid. Maintenance: 60-180 mg once daily.
SEDATION
Adult: 30-120 mg/day in 2-3 divided doses.
Child: 6 mg/kg/day or 180 mg/m2/day divided in 3 equal doses.
HYPNOTIC
Adult: 100-320 mg at bedtime. Do not admin for >2 wk for the treatment of insomnia.
PRE-OPERATIVE SEDATION
Child: 1-3 mg/kg 1-1.5 hr before procedure.
Intravenous
STATUS EPILEPTICUS
Adult: Doses of 10 mg/kg to a max of 1 g.
Child: As sodium: Neonates and children up to 12 yr: Initially, 20 mg/kg by slow IV inj then 2.5-5 mg/kg once or bid. 12-18 yr: Initially 20 mg/kg (max 1 g) by slow IV inj then 300 mg bid.
GENERALISED TONIC-CLONIC SEIZURES
Child: As sodium: Neonates: Loading dose is 20 mg/kg by slow IV inj followed by 2.5-5 mg/kg once daily either by slow IV inj or orally.
PARTIAL SEIZURES
Child: As sodium: Neonates: Loading dose is 20 mg/kg by slow IV inj followed by 2.5-5 mg/kg once daily either by slow IV inj or orally.
PRE-OPERATIVE SEDATION
Child: As sodium: 1-3 mg/kg 1-1.5 hr before procedure.
Intramuscular
EMERGENCY MANAGEMENT OF ACUTE SEIZURES
Adult: As sodium: 200 mg IM repeated after 6 hr if necessary.
Child: As sodium: 15 mg/kg IM as a single dose.
SEDATION
Adult: As sodium: 30-120 mg/day in 2-3 divided doses.
PRE-OPERATIVE SEDATION
Adult: As sodium: 100-200 mg 1-1.5 hr be
Interactions :
May enhance the hepatotoxic potential of paracetemaol overdoses. May decrease levels/effects of various CYP isoenzyme substrates e.g. teniposide, methotrexate, antipsychotics, β-blockers, calcium-channel blockers, other anticonvulsants, chloramphenicol, cimetidine, corticosteroids, ciclosporin, doxycycline, oestrogens, felbamate, griseofulvin, tacrolimus, furosemide, methadone, oral contraceptives, theophylline, TCAs, warfarin. May reduce effects of guanfacine. Reduced metabolism and or increased toxicity with chloramphenicol, felbamate, MAOIs, valproic acid. May enhance the nephrotoxic effects of methoxyflurane.
Evening primrose may reduce seizure threshold. Increased CNS depression may occur with valerian, St John's wort, kava kava, gotu kol
Phenobarbitone is a short-acting barbiturate. It depresses the sensory cortex, reduces motor activity, changes cerebellar function, and produces drowsiness, sedation and hypnosis. Its anticonvulsant property is exhibited at high doses.
Onset: Hypnosis: Oral: 20-60 min; IV: Approx 5 min.
Duration: Oral: 6-10 hr; IV: 4-10 hr.
Indication, Dosage and Frequency :
Oral
PARTIAL SEIZURES
Adult: 60-180 mg daily taken at night. Titrate dose according to patient's needs to achieve adequate control of seizures. Plasma concentrations of 15-40 mcg/ml (65-170 micromol/l) are usually required.
Child: 1 mth-12 yr: Initially, 1-1.5 mg/kg bid. Increase by 2 mg/kg daily, as required, to a maintenance dose of 2.5-4 mg/kg once or bid. 12-18 yr: Initially, 60-180 mg bid. Maintenance: 60-180 mg once daily.
GENERALISED TONIC-CLONIC SEIZURES
Adult: 60-180 mg daily taken at night. Titrate dose according to patient's needs to achieve adequate control of seizures. Plasma concentrations of 15-40 mcg/ml (65-170 micromol/l) are usually required.
Child: 1 mth-12 yr: Initially, 1-1.5 mg/kg bid. Increase by 2 mg/kg daily, as required, to a maintenance dose of 2.5-4 mg/kg once or bid. 12-18 yr: Initially, 60-180 mg bid. Maintenance: 60-180 mg once daily.
SEDATION
Adult: 30-120 mg/day in 2-3 divided doses.
Child: 6 mg/kg/day or 180 mg/m2/day divided in 3 equal doses.
HYPNOTIC
Adult: 100-320 mg at bedtime. Do not admin for >2 wk for the treatment of insomnia.
PRE-OPERATIVE SEDATION
Child: 1-3 mg/kg 1-1.5 hr before procedure.
Intravenous
STATUS EPILEPTICUS
Adult: Doses of 10 mg/kg to a max of 1 g.
Child: As sodium: Neonates and children up to 12 yr: Initially, 20 mg/kg by slow IV inj then 2.5-5 mg/kg once or bid. 12-18 yr: Initially 20 mg/kg (max 1 g) by slow IV inj then 300 mg bid.
GENERALISED TONIC-CLONIC SEIZURES
Child: As sodium: Neonates: Loading dose is 20 mg/kg by slow IV inj followed by 2.5-5 mg/kg once daily either by slow IV inj or orally.
PARTIAL SEIZURES
Child: As sodium: Neonates: Loading dose is 20 mg/kg by slow IV inj followed by 2.5-5 mg/kg once daily either by slow IV inj or orally.
PRE-OPERATIVE SEDATION
Child: As sodium: 1-3 mg/kg 1-1.5 hr before procedure.
Intramuscular
EMERGENCY MANAGEMENT OF ACUTE SEIZURES
Adult: As sodium: 200 mg IM repeated after 6 hr if necessary.
Child: As sodium: 15 mg/kg IM as a single dose.
SEDATION
Adult: As sodium: 30-120 mg/day in 2-3 divided doses.
PRE-OPERATIVE SEDATION
Adult: As sodium: 100-200 mg 1-1.5 hr be
Interactions :
May enhance the hepatotoxic potential of paracetemaol overdoses. May decrease levels/effects of various CYP isoenzyme substrates e.g. teniposide, methotrexate, antipsychotics, β-blockers, calcium-channel blockers, other anticonvulsants, chloramphenicol, cimetidine, corticosteroids, ciclosporin, doxycycline, oestrogens, felbamate, griseofulvin, tacrolimus, furosemide, methadone, oral contraceptives, theophylline, TCAs, warfarin. May reduce effects of guanfacine. Reduced metabolism and or increased toxicity with chloramphenicol, felbamate, MAOIs, valproic acid. May enhance the nephrotoxic effects of methoxyflurane.
Evening primrose may reduce seizure threshold. Increased CNS depression may occur with valerian, St John's wort, kava kava, gotu kol
PRIMIDONE
Mechanism of Action :
Primidone raises seizure thresholds and decreases excitability of neurons. It is partly metabolised to phenobarb which also exerts anticonvulsant activity.
Indication, Dosage and Frequency :
Oral
GENERALISED TONIC-CLONIC SEIZURES
Adult: Initially, 125 mg daily at bedtime, increased by 125 mg every 3 days if necessary up to 500 mg daily, given in 2 divided doses, may further increase by 250 mg every 3 days if needed. Maintenance: 0.75-1.5 g daily.
Child: Initial dose: 125 mg daily, may increase by 125 mg every 3 days if needed. Maintenance: >9 yr: Same as adult dose; 6-9 yr: 0.75-1 g daily; 2-5 yr: 500-750 mg daily; <2 yr: 250-500 mg daily.
PARTIAL SEIZURES
Adult: Initially, 125 mg daily at bedtime, increased by 125 mg every 3 days if necessary up to 500 mg daily, given in 2 divided doses, may further increase by 250 mg every 3 days if needed. Maintenance: 0.75-1.5 g daily.
Child: Initial dose: 125 mg daily, may increase by 125 mg every 3 days if needed. Maintenance: >9 yr: Same as adult dose; 6-9 yr: 0.75-1 g daily; 2-5 yr: 500-750 mg daily; <2 yr: 250-500 mg daily.
ESSENTIAL TREMOR
Adult: Initially, 50 mg daily gradually increased over 2-3 wk if necessary. Max dose: 750 mg daily.
Interactions :
Induces hepatic metabolism of many drugs; reduces efficacy of β-blockers, chloramphenicol, cimetidine, corticosteroids, furosemide, oral contraceptives, TCAs, warfarin. Increased plasma concentrations when used with valproate or phenytoin. Increased risk of osteomalacia when used with acetazolamide. May decrease serum levels of quinidine.
Primidone raises seizure thresholds and decreases excitability of neurons. It is partly metabolised to phenobarb which also exerts anticonvulsant activity.
Indication, Dosage and Frequency :
Oral
GENERALISED TONIC-CLONIC SEIZURES
Adult: Initially, 125 mg daily at bedtime, increased by 125 mg every 3 days if necessary up to 500 mg daily, given in 2 divided doses, may further increase by 250 mg every 3 days if needed. Maintenance: 0.75-1.5 g daily.
Child: Initial dose: 125 mg daily, may increase by 125 mg every 3 days if needed. Maintenance: >9 yr: Same as adult dose; 6-9 yr: 0.75-1 g daily; 2-5 yr: 500-750 mg daily; <2 yr: 250-500 mg daily.
PARTIAL SEIZURES
Adult: Initially, 125 mg daily at bedtime, increased by 125 mg every 3 days if necessary up to 500 mg daily, given in 2 divided doses, may further increase by 250 mg every 3 days if needed. Maintenance: 0.75-1.5 g daily.
Child: Initial dose: 125 mg daily, may increase by 125 mg every 3 days if needed. Maintenance: >9 yr: Same as adult dose; 6-9 yr: 0.75-1 g daily; 2-5 yr: 500-750 mg daily; <2 yr: 250-500 mg daily.
ESSENTIAL TREMOR
Adult: Initially, 50 mg daily gradually increased over 2-3 wk if necessary. Max dose: 750 mg daily.
Interactions :
Induces hepatic metabolism of many drugs; reduces efficacy of β-blockers, chloramphenicol, cimetidine, corticosteroids, furosemide, oral contraceptives, TCAs, warfarin. Increased plasma concentrations when used with valproate or phenytoin. Increased risk of osteomalacia when used with acetazolamide. May decrease serum levels of quinidine.
VALPROIC
Mechanism of Action :
Treatment of generalised epilepsy particularly w/ absence, myoclonic, tonic-clonic, atonic & mixed patterns of seizures; & partial epilepsy particularly w/ simple or complex, secondary generalised, specific syndromes (west, Lennox Gastaut). Inj Prophylaxis of febrile convulsions & tics in childn.
Treatment of generalised epilepsy particularly w/ absence, myoclonic, tonic-clonic, atonic & mixed patterns of seizures; & partial epilepsy particularly w/ simple or complex, secondary generalised, specific syndromes (west, Lennox Gastaut). Inj Prophylaxis of febrile convulsions & tics in childn.
Indication, Dosage and Frequency : Interactions :
Antiepileptics, CNS depressants, aspirin, barbiturates, warfarin, dicumarol.
Interactions between your selected drugs
Dilantin (phenytoin) and ethosuximide (Moderate Drug-Drug)
MONITOR: Succinimides may increase serum hydantoin levels. The pharmacologic and toxic effects of hydantoins may be increased. The mechanism is not fully understood, but may be related to inhibition of the hepatic metabolism of hydantoins. In addition, phenytoin has been associated with reductions in succinimide levels.
MANAGEMENT: If a succinimide and a hydantoin must be used together, close observation for evidence of altered hydantoin effect is recommended. Patients should be advised to notify their physician if they experience symptoms of possible hydantoin toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia.
Dilantin (phenytoin) and insulin (Moderate Drug-Drug)
MONITOR: The efficacy of oral hypoglycemic agents and insulin may be diminished by certain drugs, including thiazides and other diuretics, corticosteroids, estrogens, progestins, thyroid hormones, human growth hormone, phenothiazines, atypical antipsychotics, sympathomimetic amines, protease inhibitors, phenytoin, clozapine, megestrol, danazol, isoniazid, asparaginase, pegaspargase, diazoxide, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.
MANAGEMENT: Close clinical monitoring of glycemic control is recommended if these drugs are coadministered with antidiabetic agents. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen. Dose adjustments of the hypoglycemic agent may be required.
aspirin and insulin (Moderate Drug-Drug)
MONITOR: The hypoglycemic effect of insulin may be potentiated by certain drugs, including ACE inhibitors, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, disopyramide, quinine, quinidine, MAOIs, ginseng); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); and/or inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or insulin secretagogues.
MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin, particularly in patients with advanced age and/or renal impairment. The insulin dosage may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.
aspirin and clopidogrel (Moderate Drug-Drug)
MONITOR: Clopidogrel has been shown to potentiate the inhibition of platelet aggregation due to aspirin. Single-dose studies have not shown a prolongation of bleeding time when aspirin was added to clopidogrel; however, the risk of gastrointestinal (GI) bleeding may be increased. A large clinical trial reported that clopidogrel 75 mg/day plus aspirin 75 to 325 mg/day for up to 1 year was associated with a higher incidence of major GI bleeding (1.3% vs 0.7% with aspirin alone). These two medications are routinely used together for their additive antiplatelet, antistroke effect. The safety of chronic administration of aspirin or other salicylates with clopidogrel has not been established.
MANAGEMENT: Until further data are available, caution is recommended, especially in patients at risk of bleeding (i.e., GI ulceration), if clopidogrel is coadministered on a long-term basis with drugs that may cause GI lesions. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, red or black stools, or bloody or coffee-ground emesis. Patients should also be counseled to avoid any other over-the-counter salicylate products.
atorvastatin and clopidogrel (Moderate Drug-Drug)
MONITOR: The concomitant administration of atorvastatin may reduce the metabolic activation of the prodrug clopidogrel and its antiplatelet effects. The proposed mechanism is competitive inhibition of CYP450 3A4 enzymatic activity, which is responsible for the conversion of clopidogrel to its active metabolite. However, data have been conflicting. In a trial with coronary stent implant patients receiving clopidogrel 75 mg/day (n=44), the percent platelet aggregation was 34% with no atorvastatin, 58% with atorvastatin 10 mg, 74% with 20 mg, and 89% with 40 mg. Results from an in vitro study suggest that equimolar concentrations of atorvastatin inhibit clopidogrel metabolism by more than 90 %. However, in a post hoc analysis of a trial with percutaneous coronary intervention patients, no statistical differences in the incidence of bleeding, stroke, myocardial infarction, or death were found at 1 year with concomitant administration of clopidogrel 75 mg/day and CYP450 3A4-metabolized HMG-CoA reductase inhibitors (n=1001, atorvastatin, lovastatin, simvastatin, cerivastatin) or other statins (n=158, pravastatin, fluvastatin).
MANAGEMENT: Until more information is available, monitoring for altered efficacy of clopidogrel may be advisable if atorvastatin is coadministered with clopidogrel. Pravastatin, fluvastatin, and rosuvastatin are not metabolized by CYP450 3A4 and are theoretically not expected to interact with clopidogrel.
Dilantin (phenytoin) and aspirin (Minor Drug-Drug)
In vitro studies suggest that salicylates may displace phenytoin from plasma protein-binding sites. The potential for phenytoin toxicity exists. The clinical significance is unknown. One case of phenytoin toxicity has been reported in a patient taking aspirin. However, clinical studies in healthy subjects and epileptic patients (taking phenytoin and 1500 mg aspirin/day) have not reported significant pharmacokinetic changes, adverse effects, or loss of seizure control.
Dilantin (phenytoin) and clopidogrel (Minor Drug-Drug)
In vitro studies have shown that high concentrations of clopidogrel inhibit CYP450 2C9 isoenzymes. The metabolism of drugs which are substrates for this enzyme may be decreased, potentiating toxicity of the substrate drug. The clinical significance and magnitude of this interaction is not known. Dose adjustments may be necessary if an interaction is suspected.
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MONITOR: Succinimides may increase serum hydantoin levels. The pharmacologic and toxic effects of hydantoins may be increased. The mechanism is not fully understood, but may be related to inhibition of the hepatic metabolism of hydantoins. In addition, phenytoin has been associated with reductions in succinimide levels.
MANAGEMENT: If a succinimide and a hydantoin must be used together, close observation for evidence of altered hydantoin effect is recommended. Patients should be advised to notify their physician if they experience symptoms of possible hydantoin toxicity, including drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia.
Dilantin (phenytoin) and insulin (Moderate Drug-Drug)
MONITOR: The efficacy of oral hypoglycemic agents and insulin may be diminished by certain drugs, including thiazides and other diuretics, corticosteroids, estrogens, progestins, thyroid hormones, human growth hormone, phenothiazines, atypical antipsychotics, sympathomimetic amines, protease inhibitors, phenytoin, clozapine, megestrol, danazol, isoniazid, asparaginase, pegaspargase, diazoxide, temsirolimus, as well as pharmacologic dosages of nicotinic acid and adrenocorticotropic agents. These drugs may interfere with blood glucose control because they can cause hyperglycemia, glucose intolerance, new-onset diabetes mellitus, and/or exacerbation of preexisting diabetes.
MANAGEMENT: Close clinical monitoring of glycemic control is recommended if these drugs are coadministered with antidiabetic agents. Likewise, patients should be observed for hypoglycemia when these drugs are withdrawn from their therapeutic regimen. Dose adjustments of the hypoglycemic agent may be required.
aspirin and insulin (Moderate Drug-Drug)
MONITOR: The hypoglycemic effect of insulin may be potentiated by certain drugs, including ACE inhibitors, anabolic steroids, fibrates, monoamine oxidase inhibitors (MAOIs), salicylates, selective serotonin reuptake inhibitors (SSRIs), sulfonamides, disopyramide, propoxyphene, quinine, quinidine, and ginseng. These drugs may increase the risk of hypoglycemia by enhancing insulin sensitivity (ACE inhibitors, fibrates, ginseng); stimulating insulin secretion (salicylates, disopyramide, quinine, quinidine, MAOIs, ginseng); increasing peripheral glucose utilization (SSRIs, insulin-like growth factor); and/or inhibiting gluconeogenesis (SSRIs, MAOIs, insulin-like growth factor). Clinical hypoglycemia has been reported during use of some of these agents alone or with insulin and/or insulin secretagogues.
MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if these drugs are coadministered with insulin, particularly in patients with advanced age and/or renal impairment. The insulin dosage may require adjustment if an interaction is suspected. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it occurs. Patients should be observed for loss of glycemic control when these drugs are withdrawn.
aspirin and clopidogrel (Moderate Drug-Drug)
MONITOR: Clopidogrel has been shown to potentiate the inhibition of platelet aggregation due to aspirin. Single-dose studies have not shown a prolongation of bleeding time when aspirin was added to clopidogrel; however, the risk of gastrointestinal (GI) bleeding may be increased. A large clinical trial reported that clopidogrel 75 mg/day plus aspirin 75 to 325 mg/day for up to 1 year was associated with a higher incidence of major GI bleeding (1.3% vs 0.7% with aspirin alone). These two medications are routinely used together for their additive antiplatelet, antistroke effect. The safety of chronic administration of aspirin or other salicylates with clopidogrel has not been established.
MANAGEMENT: Until further data are available, caution is recommended, especially in patients at risk of bleeding (i.e., GI ulceration), if clopidogrel is coadministered on a long-term basis with drugs that may cause GI lesions. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, red or black stools, or bloody or coffee-ground emesis. Patients should also be counseled to avoid any other over-the-counter salicylate products.
atorvastatin and clopidogrel (Moderate Drug-Drug)
MONITOR: The concomitant administration of atorvastatin may reduce the metabolic activation of the prodrug clopidogrel and its antiplatelet effects. The proposed mechanism is competitive inhibition of CYP450 3A4 enzymatic activity, which is responsible for the conversion of clopidogrel to its active metabolite. However, data have been conflicting. In a trial with coronary stent implant patients receiving clopidogrel 75 mg/day (n=44), the percent platelet aggregation was 34% with no atorvastatin, 58% with atorvastatin 10 mg, 74% with 20 mg, and 89% with 40 mg. Results from an in vitro study suggest that equimolar concentrations of atorvastatin inhibit clopidogrel metabolism by more than 90 %. However, in a post hoc analysis of a trial with percutaneous coronary intervention patients, no statistical differences in the incidence of bleeding, stroke, myocardial infarction, or death were found at 1 year with concomitant administration of clopidogrel 75 mg/day and CYP450 3A4-metabolized HMG-CoA reductase inhibitors (n=1001, atorvastatin, lovastatin, simvastatin, cerivastatin) or other statins (n=158, pravastatin, fluvastatin).
MANAGEMENT: Until more information is available, monitoring for altered efficacy of clopidogrel may be advisable if atorvastatin is coadministered with clopidogrel. Pravastatin, fluvastatin, and rosuvastatin are not metabolized by CYP450 3A4 and are theoretically not expected to interact with clopidogrel.
Dilantin (phenytoin) and aspirin (Minor Drug-Drug)
In vitro studies suggest that salicylates may displace phenytoin from plasma protein-binding sites. The potential for phenytoin toxicity exists. The clinical significance is unknown. One case of phenytoin toxicity has been reported in a patient taking aspirin. However, clinical studies in healthy subjects and epileptic patients (taking phenytoin and 1500 mg aspirin/day) have not reported significant pharmacokinetic changes, adverse effects, or loss of seizure control.
Dilantin (phenytoin) and clopidogrel (Minor Drug-Drug)
In vitro studies have shown that high concentrations of clopidogrel inhibit CYP450 2C9 isoenzymes. The metabolism of drugs which are substrates for this enzyme may be decreased, potentiating toxicity of the substrate drug. The clinical significance and magnitude of this interaction is not known. Dose adjustments may be necessary if an interaction is suspected.
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