Treatment of epilepsy should begin with a single antiepileptic drug (AED), increasing its dosage gradually until seizures are controlled or adverse effects become intolerable. If seizures persist, specialists generally recommend trying at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs concurrently. When used for the appropriate seizure type, AEDs are roughly equivalent in efficacy. Drug choice is usually based on factors such as ease of use, adverse effects, drug interactions, presence of comorbidities, and cost.

View the Comparison Table: Some Oral Antiepileptic Drugs

The treatment of atrial fibrillation includes anticoagulation, rate control, and rhythm control. New US guidelines for the management of atrial fibrillation have recently been published.

Treatment of epilepsy should begin with a single drug, increasing the dosage gradually until seizures are controlled or adverse effects become unacceptable. If seizures persist, expert clinicians generally prescribe at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs at the same time. When used for the appropriate seizure type, antiepileptic drugs are roughly equivalent in efficacy. The choice of drug is usually based on factors such as ease of use, adverse effects, interactions with other drugs, presence of comorbid conditions and cost.

The FDA has approved ezogabine (ee-ZOE-ga-been; Potiga – GSK/Valeant) for oral adjunctive treatment of partial-onset seizures in adults. Ezogabine is available in Europe as retigabine (Trobalt).

Attention-deficit/hyperactivity disorder (ADHD) is a disruptive behavior disorder that occurs in about 5% of school-age children, most often in boys, and frequently persists into young adulthood.

The FDA has approved vigabatrin (vye gá ba trin; Sabril – Lundbeck) for oral use as add-on therapy for complex partial seizures in adults who are refractory to several antiepileptic drugs and as monotherapy for infantile spasms. Vigabatrin has been available in other countries for many years. Because of its potential for retinal toxicity, it will be available in the US only through a restricted distribution program called SHARE (Support, Help and Resources for Epilepsy). Prescribers and pharmacists distributing the drug must register, and patients must undergo visual field testing.

The FDA has approved lacosamide (Vimpat - UCB Pharma) for oral or intravenous (IV) use as add-on therapy in adults with partial-onset seizures.

Rufinamide (Banzel - Eisai), a triazole derivative structurally unrelated to other marketed antiepileptic drugs (AEDs), has been approved by the FDA for treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients ≥4 years old.

A recent letter to the editor of the Annals of Internal Medicine documented a single case of myopathy apparently due to an interaction between simvastatin (Zocor, and others) and green tea. Since it became available generically, simvastatin has surpassed atorvastatin (Lipitor) as the best selling statin. As such, it is probably the most common cause of statin-induced myopathy, which is often a result of drug interactions.

Peptic ulcers caused by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) are mainly gastric ulcers. The greater the number of office visits and the longer the counseling time, the higher the smoking cessation rates have been.

Peptic ulcers caused by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) are mainly gastric ulcers. Most duodenal and other gastric ulcers are caused by the gram-negative bacillus Helicobacter pylori. Gastroesophageal reflux disease (GERD) is caused by gastric acid reflux into the esophagus. Drugs that suppress gastric acid production are the primary treatment for GERD and peptic ulcers.

A reader expressed disappointment that our recent listing of “Some Warfarin Drug Interactions”1 did not include acetaminophen. Perhaps it should have. Acetaminophen can increase the anticoagulant effect of warfarin, particularly with continued use, but it does so inconsistently. The mechanism of this interaction has not been established, but may be related to an acetaminophen metabolite inhibiting vitamin K-epoxide reductase, the target for warfarin’s anticoagulant effect.2

Patient susceptibility varies, possibly on a genetic basis; occasional use of acetaminophen generally has little or no effect on the international normalized ratio (INR) in patients on chronic warfarin therapy, but in some, even a few grams of the drug may cause a dramatic increase in INR. One study in healthy subjects found no effect of acetaminophen 4 g per day for 2 weeks, while another study in patients with the same acetaminophen dose for the same period of time found a moderate increase in INR.3,4 It might be prudent to monitor INR in patients on chronic warfarin therapy more closely than usual when they take more than 2 g per day of acetaminophen for more than a few days.

1. Pharmacogenetic-based dosing of warfarin. Med Lett Drugs Ther 2008; 50:39.
2. HH Thijssen et al. Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle. Thromb Haemost 2004; 92:797.
3. D Kwan et al. The effects of acetaminophen on pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999; 39:68.
4. I Mahe et al. Paracetamol: A haemorrhagic risk factor in patients on warfarin. Br J Clin Pharmacol 2005; 59:371.

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Treatment of epilepsy should begin with a single drug, increasing the dosage gradually until seizures are controlled or adverse effects become unacceptable. If seizures continue and further dosage increases appear inadvisable because of adverse effects, most Medical Letter consultants generally prescribe at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs at the same time. Most antiepileptic drugs initially approved by the FDA only as adjunctive therapy for partial seizures may also be effective for other types of seizures and as monotherapy. Studies suggest that when used for the appropriate seizure type, antiepileptic drugs are roughly equivalent in efficacy. The choice of a drug is usually based on factors such as ease of use, adverse effects and cost.

Warfarin sodium (Coumadin, and others) and other coumarin anticoagulants prevent thrombosis, but patient response is highly variable and overanticoagulation can lead to hemorrhage. Genotyping patients for single nucleotide polymorphisms (SNPs) that affect coumarin metabolism and sensitivity may help clinicians estimate the therapeutic warfarin dose. The FDA has added a note to warfarin labeling recommending lowrange doses for patients with such genetic variations. Commercial tests for these variants are now available and cost about $500 per test.

The drugs of choice for treatment of some fungal infections are listed in the tables. Some of the indications and dosages recommended here have not been approved by the FDA. Other guidelines are available from the Infectious Diseases Society of America (www.idsociety.org).

Treatment of epilepsy should begin with a single drug, increasing the dosage gradually until seizures are controlled or adverse effects become unacceptable. If seizures continue and further dosage increases appear inadvisable because of adverse effects, most Medical Letter consultants generally prescribe at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs at the same time. Most antiepileptic drugs initially approved by the FDA only as adjunctive therapy for partial seizures may also be effective for other types of seizures and as monotherapy.

Pregabalin (Lyrica - Pfizer), a structural analog of gamma-aminobutyric acid (GABA) similar to gabapentin (Neurontin - Pfizer, and others), which recently became available generically, has been approved by the FDA for treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN), and for adjunctive treatment of partial onset seizures in adults with epilepsy.

The FDA recently cleared the AmpliChip CYP450 Test (Roche), which analyzes blood-derived DNA to detect genetic variations in the activity of cytochrome P450 (CYP) enzymes CYP2D6 and CYP2C19 and determines the metabolizer status of the patient. The test is intended to help guide clinicians in prescribing individualized drug therapy. About 25% of all drugs, including many antidepressants and antipsychotics, are substrates of either CYP2D6 or CYP2C19. The test is being promoted initially to psychiatrists.

Serious adverse interactions between drugs continue to be reported. Many of these are due to inhibition or induction of cytochrome P450 (CYP) enzymes, particularly CYP3A4. CYP3A is thought to be involved in the metabolism of more than 50 percent of currently prescribed drugs.2 CYP3A4, which is more abundantly expressed than CYP3A5, accounts for most CYP3A activity in vivo.

Erlotinib (Tarceva) is the second oral epidermal growth factor receptor (EGFR) inhibitor to become available in the US for treatment of advanced refractory NSCLC. In clinical trials, erlotinib produced a response rate of only 8.9%, but increased median survival from 4.7 to 6.7 months. Patients who had never smoked and those with EGFR-positive tumors survived longer. Erlotinib is generally well tolerated; diarrhea and rash are the most common adverse effects.

The drugs of choice for treatment of some fungal infections are listed in the table that begins on page 8. Some of the indications and dosages recommended here have not been approved by the FDA.

Patients with frequent, severe or disabling migraine headaches may benefit from taking a drug to prevent the attacks. Beta-blockers traditionally have been the prophylactic treatment of choice, but in recent years some antiepileptic drugs such as valproate (Depakote, and others) and topiramate (Topamax) have also been used for this indication. Valproate was approved by the FDA for such use in 1996. Now topiramate has also been approved.

Tinidazole (Tindamax - Presutti Labs), an oral antiprotozoal drug similar to metronidazole (Flagyl, and others), has been approved by the FDA for treatment of trichomoniasis in adults and for treatment of giardiasis, intestinal amebiasis and amebic liver abcess in adults and children more than 3 years old. Tinidazole has been widely used outside of the US for decades under the trade name Fasigyn (Pfizer).

Telithromycin (Ketek - Aventis) has been approved by the FDA for oral treatment of mild to moderate community-acquired pneumonia, acute exacerbations of chronic bronchitis and acute bacterial sinusitis in patients age 18 and older. The drug is the first in a new class of antibiotics, the ketolides, derived from the macrolide erythromycin. Telithromycin has been marketed in Europe since 2001.

Three types of analgesic drugs are available: non-opioids, including aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; opioids; and adjuvant drugs that are not usually thought of as analgesics, such as antidepressants, which can act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain. Combining two different types of analgesics may provide an additive analgesic effect without necessarily increasing adverse effects.

Modafinil (Provigil - Cephalon; Alertec - Draxis in Canada), first approved by the FDA in 1999 for treatment of excessive daytime sleepiness associated with narcolepsy (Medical Letter 1999; 41:30), has now also been approved for treatment of patients with excessive sleepiness due to obstructive sleep apnea/hypopnea syndrome (OSAHS) or shift work sleep disorder (SWSD) (DSM-IV, text revision, Washington, DC: American Psychiatric Association, 2000, page 622).

Most peptic ulcers not caused by nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with infection of the gastric mucosa by the gram-negative bacilli Helicobacter pylori. The majority of NSAID-related ulcers are gastric. H. pylori infection causes both duodenal and gastric ulcers. Eradication of H. pylori promotes healing and markedly decreases recurrence of both duodenal and gastric ulcers (A Shiotamni and DY Graham, Med Clin North Am 2002; 86:1447; FKL Chan and WK Leung, Lancet 2002; 360:933). The first step in the management of peptic ulcers is the diagnosis and treatment of H. pylori.

Changes caused by one drug in the absorption, distribution, metabolism or excretion of another may lead to a pharmacokinetic adverse drug interaction (DN Juurlink et al, JAMA 2003; 289:1652). Additive drug interactions, such as vasodilation caused by both sildenafil (Viagra) and nitrates, can also have adverse effects.

Treatment of epilepsy should begin with a single drug, increasing the dosage gradually until seizures are controlled or adverse effects become unacceptable. If seizures continue and further dosage increases appear inadvisable because of adverse effects, most Medical Letter consultants generally prescribe at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs at the same time. Most antiepileptic drugs initially approved by the FDA only for adjunctive therapy are probably also effective as monotherapy. Many of the drugs used to treat epilepsy interact with each other (see table beginning on page 63) and with other drugs; for interactions with other drugs, see The Medical Letter Handbook of Adverse Drug Interactions, 2003. The treatment of status epilepticus is not included here.

When patents expire on brand-name drugs and generic formulations become available, patients and managed care organizations may express a preference for the lower-cost generics. Are they equivalent to the brand-name product?

Imatinib mesylate (STI-571; Gleevec - Novartis), an oral tyrosine kinase inhibitor, has received accelerated approval from the FDA for treatment of all phases of chronic myeloid leukemia (CML) after interferon has failed.

Zonisamide (Zonegran - Elan Pharma), a sulfonamide chemically unrelated to other antiepileptic drugs, has been approved by the FDA for adjunctive use in adults with partial seizures. Zonisamide has been available in Japan for more than 10 years.

Pantoprazole, the fourth benzimidazole proton pump inhibitor to become available in the United States, has been marketed for short-term oral treatment of erosive gastroesophageal reflux disease (GERD).

Oxcarbazepine, which is chemically similar to carbamazepine, and levetiracetam, a pyrrolidine acetamide chemically unrelated to other antiepileptic drugs, are the sixth and seventh drugs approved by the US Food and Drug Administration in the last five years for oral use in partial seizures.

Rabeprazole, a benzimidazole proton pump inhibitor similar to omeprazole and lansoprazole, has been approved by the FDA for treatment of duodenal ulcers, healing and maintenance treatment of erosive or ulcerative gastroesophageal reflux disease, and for long-term treatment of chronic hypersecretory conditions, including Zollinger-Ellison syndrome

When patents expire on brand-name drugs, generic formulations become available that often cost much less. Some physicians, however, hesitate to prescribe the less expensive drug because of concerns about the quality of generic formulations.

Three types of analgesic drugs are available: first, non-opioids, including aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; second, opioids; and third, some drugs not usually thought of as analgesics, which act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain.

Clopidogrel bisulfate (Plavix - Bristol-Myers Squibb/Sanofi), a new thienopyridine antiplatelet agent similar to ticlopidine (Ticlid - Medical Letter, 34:65, 1992), has been approved by the US Food and Drug Administration (FDA) for secondary prevention of myocardial infarction, stroke and other vascular events.

Quetiapine (Seroquel - Zeneca), a dibenzothiazepine derivative, has been approved by the FDA for treatment of schizophrenia and other psychotic disorders. It is a new addition to the 'atypical' antipsychotics, which include olanzapine (Zyprexa - Medical Letter, 39:5, 1997), risperidone (Risperdal) and clozapine (Clozaril). Atypical antipsychotic drugs generally are less likely to cause extrapyramidal symptoms than older drugs such as haloperidol (Haldol, and others) or the phenothiazines.

Bromfenac sodium (Duract - Wyeth-Ayerst), a nonsteroidal anti-inflammatory drug (NSAID), has been approved by the US Food and Drug Administration (FDA) and is being heavily advertised as an alternative to narcotics for short-term treatment of pain.

The drugs of choice for treatment of deep fungal infections are listed in the table below. Some of the indications and dosages recommended here have not been approved by the FDA.

Topiramate (Topamax - Ortho-McNeil) has been approved by the US Food and Drug Administration (FDA) for oral use as an adjunct to other drugs in adult patients with partial seizures. Since this diagnostic category includes the largest number of patients with refractory epilepsy, new drugs with antiepileptic activity are usually tried first for this indication. Topiramate (toe pyre' a mate) is a structurally unique agent chemically related to the D-enantiomer of fructose.

Zafirlukast (za fir loo kast; Accolate - Zeneca), the first leukotriene receptor anta-gonist approved by the US Food and Drug Administration, is now being heavily promoted for oral maintenance treatment of chronic asthma in patients more than 12 years old. It is not recommended for treatment of acute asthma.

The drugs of choice for treatment of deep fungal infections are listed in the table on page 101. Some of the indications and dosages recommended here have not been approved by the US Food and Drug Administration. More detailed guidelines are available from the Infectious Diseases Society of America (J Sobel et al, Clin Infect Dis, volume 30, April 2000).

Itraconazole (Sporanox - Janssen), an oral antifungal triazole that has been available in the USA since 1992 for treatment of deep fungal infections (Medical Letter, 35:7, 1993), is now being marketed for treatment of dermatophyte infections of the toenails, with or without fingernail involvement.

Patients may be asking their physicians about use of histamine H2-receptor antagonists for treatment and prevention of heartburn. Cimetidine and famotidine have recently been released for over-the-counter sale and are being heavily advertised on television and in the print media.

Lamotrigine (la mo tri jeen; Lamictal - Burroughs Wellcome), a phenyltriazine derivative, has been approved by the US Food and Drug Administration for use in addition to other antiepileptic drugs in adults with partial seizures. Since this diagnostic category includes the largest number of patients with intractable epilepsy, new drugs with antiepileptic activity are usually tried first for this indication. Lamotrigine was first marketed abroad in 1990 and is now available in more than 50 other countries.

Fluvoxamine (Luvox - Solvay), a selective serotonin reuptake inhibitor (SSRI), has been approved for treatment of obsessive-compulsive disorder (OCD) by the US Food and Drug Administration. Fluoxetine (Prozac), another SSRI antidepressant, and clomipramine (Anafranil), a tricyclic antidepressant that also inhibits serotonin reuptake, are the only other drugs available for this indication in the USA. Antidepressants that do not inhibit serotonin reuptake have not been effective for treatment of this condition.

Although lithium (Eskalith, and others) is the standard treatment for bipolar (manic-depressive) disorder, 20% to 40% of patients do not respond adequately or cannot tolerate its adverse effects (Medical Letter, 33:43, 1991). Results of recent studies suggest that valproate (Depakene - valproic acid; Depakote - divalproex sodium), a widely used anticonvulsant (Medical Letter, 31:1, 1989), might be an effective alternative. Other anticonvulsants, particularly carbamazepine (Tegretol, and others), have also been used as second-line drugs for treatment of mania and other psychiatric disorders (C Van Valkenburg et al, Drugs, 44:326, 1992; PE Keck, Jr et al, J Neuropsychiatry Clin Neurosci, 4:395, 1992).

Most peptic ulcers not caused by nonsteroidal anti-inflammatory drugs (NSAIDs) are now thought to be associated with infection of the gastric mucosa by the gram-negative bacilli Helicobacter pylori (NIH Consensus Development Panel, JAMA, 272:65, July 6, 1994). NSAID-related ulcers are usually gastric. H. pylori have been associated with both duodenal and gastric ulcers.

Gabapentin (Neurontin - Parke-Davis), a cyclohexane acetic acid derivative, has been approved by the US Food and Drug Administration for use in addition to other antiepileptic drugs in patients with partial (focal) seizures with or without secondary generalization. Since this diagnostic category includes the largest number of patients with intractable epilepsy, new drugs with antiepileptic activity are generally tried first for this indication.

Felbamate (Felbatol - Wallace Laboratories), a phenyl dicarbamate structurally similar to meprobamate (Equanil, and others), was recently approved by the US Food and Drug Administration for use alone or with other drugs in adults with partial seizures with or without secondary generalization. It was also approved for use in addition to other drugs in children with the multiple types of seizures associated with the Lennox-Gastaut syndrome, a severe epileptic encephalopathy.

Paroxetine (Paxil - SmithKline Beecham), a new selective serotonin reuptake inhibitor (SSRI), is now available in the USA. Two other SSRIs, fluoxetine (Prozac - Medical Letter, 30:45, 1988; 32:83, 1990) and sertraline (Zoloft - Medical Letter, 34:47, 1992), were approved previously.

Clozapine (Clozaril - Sandoz), an antipsychotic drug, was first marketed in the USA three years ago (Medical Letter, 32:3, 1990). Because of its hematological toxicity, the US Food and Drug Administration approved the drug only for patients with schizophrenia who cannot tolerate or do not respond to standard antipsychotic drugs.

Itraconazole (Sporanox - Janssen), an antifungal triazole, has been approved by the US Food and Drug Administration (FDA) for oral treatment of histoplasmosis and blastomycosis. These two endemic mycoses occur both in normal hosts and in immunocompromised patients, such as those with AIDS (RW Bradsher, Clin Infect Dis, 14:S82, 1992; LJ Wheat, Clin Infect Dis, 14:S91, 1992).

Three types of analgesic drugs are available in the USA: first, aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen; second, opioids; and third, drugs not usually thought of as analgesics, which act as adjuvants when given with NSAIDs or opioids, or have analgesic activity of their own in some types of pain. (American Pain Society, Principles of analgesic Use, 3rd ed, Skokie, illinois: American pain society, 1992).

Teniposide (ten i poe' side; VM 26; Vumon - Bristol), an anticancer drug that has been under investigation in the USA for 20 years, has now been approved for use in combination induction treatment of refractory acute lymphoblastic leukemia (ALL) in children. A semisynthetic derivative of podophyllotoxin, teniposide is chemically related to etoposide (VePesid - Medical Letter, 26:48, 1984).

Drugs that accelerate healing and prevent relapse or reurrence of peptic ulcers act either by decreasing gastric acidity or by enhancing mucosal defense mechanisms. Risk factors that may cause breakdown of mucosal defenses include the use of aspirinor other nonsteroidal anti-inflammatory drugs (NSAIDs) and the presence of Helicobacter pylori bacterial in the gastric antrum (AH Soll, Engl J Med, 322:909, 1990; WL Peterson, N Engl J Med, 324:1043, 1991).

Doxacurium (Nuromax - Burroughs Wellcome), a new, long-acting, nondepolarizing neuromuscular blocking agent, is now available in the USA for use as a skeletal muscle relaxant during general anesthesia and for endotracheal intubation. Although small decreases in heart rate and mean arterial pressure occur in some patients who receive doxacurium, clinical studies have found no adverse cardiovascular effects in patients with heart disease receiving up to three times the usual effective dose (CM Stoops et al, Anesthesiology, 69:365, 1988; DJ Murray et al, Anesthesiology, 69:472, 1988; RS Emmott et al, Br J Anaesth, 65:480, 1990). As with pipecuronium, which it closely resembles in activity, the duration of block is prolonged in patients with renal failure (JN Cashman et al, Br J Anaesth, 64:186, 1990; DR Cook et al, Anesth Analg, 72:145, 1991).

The Norplant System (Wyeth-Ayerst) for subdermal delivery of the synthetic progestin levonorgestrel was recently approved by the US Food and Drug Administration for use as a long-term contraceptive.

Some commonly used systemic drugs that may cause pulmonary toxicity are listed in the table below. These adverse effects may sometimes be difficult to distinguish from the underlying disease (JAD Cooper, Jr et al, Am Rev Respir Dis, 133:321, 488, 1986). Pulmonary effects that are part of a generalized reaction or are indirect effects of drugs - on respiratory muscles, for example, or on the immune system - are not included here.

Fluconazole (Diflucan - Roerig), an antifungal azole, was recently approved by the US Food and Drug Administration for oral and intravenous (IV) treatment of cryptococcal meningitis and various forms of candidiasis. Both cryptococcal meningitis and candidiasis occur frequently in patients with AIDS, organ transplants, or cancer.