The FDA has approved daclatasvir (Daklinza – BMS), an oral direct-acting antiviral drug, for use with sofosbuvir (Sovaldi) for treatment of chronic hepatitis C virus (HCV) genotype 3 infection. Daclatasvir is the first drug approved for this indication that does not require the addition of interferon or ribavirin. It is approved in Japan and Europe in combination with other drugs for treatment of HCV genotypes 1-4.

The FDA recently announced changes in the labeling of the hepatitis C drugs Sovaldi (sofosbuvir) and Harvoni (sofosbuvir/ledipasvir) to warn about a risk of serious and potentially fatal bradycardia when either drug is taken with the antiarrhythmic drug amiodarone (Cordarone, and others).1 Symptomatic bradycardia was reported following initiation of treatment with Harvoni or with Sovaldi plus simeprevir (Olysio) or the investigational antiviral drug daclatasvir in 9 patients already taking amiodarone; it occurred within 24 hours of starting hepatitis C therapy in 6 patients and within 2-12 days in 3 others. One patient died of cardiac arrest and 3 required pacemaker implantation. In 3 patients who continued taking amiodarone, rechallenge with Harvoni or Sovaldi resulted in recurrence of symptomatic bradycardia. In another patient, rechallenge 8 weeks after stopping amiodarone did not result in bradycardia.

The mechanism of this effect is unknown. Factors possibly contributing to the cardiac events include concomitant beta blocker therapy (in 7 patients) and preexisting cardiac and hepatic disease. Hepatic impairment increases the risk of cardiac conduction abnormalities and could increase adverse effects of amiodarone, which is metabolized by the liver.2 Use of sofosbuvir without amiodarone has not been associated with significant bradycardia.

The new labels warn that sofosbuvir and amiodarone should not be taken concurrently. If concomitant use is necessary, cardiac monitoring in an inpatient setting is recommended for the first 48 hours. Daily monitoring of heart rate, either at home or in an outpatient setting, should continue for at least the first 2 weeks of treatment. Amiodarone has a very long half-life, and its effects may persist for weeks to months after discontinuation.

1. FDA. FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir Harvoni or Sovaldi in combination with another direct acting antiviral drug. Available at http://www.fda.gov. Accessed April 2, 2015.
2. U Klotz. Antiarrhythmics: elimination and dosage considerations in hepatic impairment. Clin Pharmacokinet 2007; 46:985.

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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.

Dronedarone (Multaq – Sanofi), an analog of amiodarone, was approved by the FDA in 2009 for oral treatment of paroxysmal or persistent (non-permanent) atrial fibrillation or atrial flutter. Amiodarone (Cordarone, and others) is more effective for this indication, but its use is often limited by its adverse effects, including thyroid and pulmonary toxicity.

The FDA has required the manufacturer of the secondgeneration antipsychotic quetiapine (Seroquel) to add a warning to the labeling saying that use of the drug should be avoided in combination with other drugs that prolong the electrocardiographic QTc interval (Table 1). The warning is based only on postmarketing reports of QT-interval prolongation in patients who overdosed on the drug, had concomitant illness, or were taking other drugs known to cause electrolyte imbalances or increase the QT interval. QT prolongation can lead to torsades de pointes, a potentially fatal cardiac arrhythmia.

The FDA has announced changes in the labeling of simvastatin to reduce the risk of myopathy. These changes include limiting the use of the 80-mg maximum dose to patients who have been taking it for 12 months or more without evidence of myopathy and new recommendations for use of simvastatin with other drugs. Simvastatin is available alone (Zocor, and others) and in combination with ezetimibe (Vytorin) and with niacin (Simcor).

The FDA and the manufacturer (Sanofi-Aventis) have warned healthcare professionals that use of dronedarone (Multaq), an analog of amiodarone (Cordarone, and others) approved in 2009 for treatment of atrial fibrillation,1,2 has been associated with "several" cases of severe liver injury and hepatic failure, including two that required liver transplants. Both transplants were in women about 70 years old; one had taken the drug for 4.5 months and the other for 6 months. According to the FDA, 147,000 patients have taken dronedarone.3 A new warning in the package insert recommends monitoring hepatic enzymes, especially during the first 6 months of treatment.

1. Dronedarone (Multaq) for atrial fibrillation. Med Lett Drugs Ther 2009; 51:78.

2. Treatment of atrial fibrillation. Treat Guidel Med Lett 2010; 8:65.

3. FDA drug safety podcast for healthcare professionals: severe liver injury associated with the use of dronedarone (marketed as Multaq). Available at www.fda.gov. Accessed February 24, 2011.

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The treatment of atrial fibrillation includes ventricular rate control, anticoagulation, conversion to normal sinus rhythm and maintenance of sinus rhythm. The choice of therapies that can achieve these goals is discussed in the text that follows. Some drugs are recommended here for indications that have not been approved by the FDA.

Dronedarone (Multaq - Sanofi-Aventis) has been approved by the FDA for oral treatment of atrial fibrillation and flutter. Amiodarone (Cordarone, and others) is the most effective drug for this indication, but has considerable toxicity.

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.

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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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 common cardiac arrhythmias are listed in Tables 1 and 2. Some drugs are recommended for indications that have not been approved by the FDA.

The physiologic changes that occur with aging can affect the pharmacokinetics and pharmacodynamics of many prescription and over-the-counter drugs, increasing the likelihood of adverse effects.

Tipranavir (Aptivus - Boehringer Ingelheim), a new protease inhibitor, has received accelerated approval from the FDA. It must be given with ritonavir (Norvir). The combination is indicated for use with other antiretrovirals to treat HIV infection in highly treatment-experienced adults who have ongoing viral replication or in those with HIV strains known to be resistant to multiple protease inhibitors.

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.

New guidelines from The National Cholesterol Education Program recommend, as a therapeutic option, lowering treatment goals for LDL cholesterol (LDL-C) from <100 mg/dL to <70 mg/dL for patients at very high risk for coronary heart disease and from 130 mg/dL to <100 mg/dL for those at moderately high risk. A likely consequence of these recommendations is increased use of statins and use of higher doses with a concomitant increase in adverse effects.

The drugs of choice for treatment of common cardiac arrhythmias are listed in the table that begins on the next page; some drugs are recommended for indications for which they have not been approved by the US FDA. The dosages and adverse effects of each drug are listed in the table that begins on page 80. Antiarrhythmic drugs may themselves cause arrhythmias, which can be fatal. Some of these drugs may increase rather than decrease mortality, especially in patients with structural heart disease.

Vardenafil (Levitra -Bayer) is the second oral drug approved by the FDA for treatment of erectile dysfunction. Sildenafil (Viagra - Medical Letter 1998; 40:51), the first oral drug, has been available for 5 years. Pharmacokinetics, effectiveness, adverse effects, dosage and cost of the new drug are reviewed. Whether it offers any benefits over sildenafil is discussed.

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.

Ever-increasing specialization has made it difficult for many physicians to keep up with therapeutic standards in intensive-care units (ICUs). This issue of Treatment Guidelines offers current recommendations for use of cardiovascular drugs in the ICU for treatment of hypertensive emergencies; shock, cardiac arrest or decompensated heart failure; and ventricular arrhythmias.

Dofetilide (Tikosyn - Pfizer), a new methanesulfonamide antiarrhythmic drug, has recently been marketed for oral treatment of atrial fibrillation and flutter.

Amprenavir is the fifth protease inhibitor to become available for treatment of HIV infection. It was approved by the FDA for use with other drugs in the treatment of HIV-infected adults and children at least four years old.

Cardiologist now emphasize the importance of neurohormonal as well as hemodynamic factors in the pathophysiology of chronic heart failure (JN Cohn, N Engl J Med, 335:490, August 15, 1996). Drugs that act on different mechanisms are commonly used together.

Sotalol (hydrochloride (Betapace -Berlex; Sotacor -Bristol Laboratories of Canada), an antiarrhythmic drug that prolongs repolarization (Class III) and also has beta-adrenergic-blocking activity (Class II), was recently approved by the US Food and Drug Administration (FDA) for oral treatment of life-threatening ventricular arrhythmias.

Flecainide (Tambocor -3M Pharmaceuticals), first introduced in 1985 for treatment of ventricular arrhythmias, was recently approved by the US Food and Drug Administration for oral use to prevent supraventricular arrhythmias. The indications for using flecainide to treat ventricular arrhythmias were limited after a controlled trial found that post-myocardial infarction patients with asymptomatic ventricular arrhythmias who took the drug had twice as high a mortality rate as patients who took placebo (DS Echt et al, N Engl Med, 324:781, 1991).

Cardiac arrest may be due to tachyarrhythmias, bradyarrhythmias, or asystole. Without treatment, permanent damage to the cerebral cortex usually begins within five minutes and is complete in ten. After cardiopulmonary resuscitation (CPR) has been started and electrical defibrillation, when indicated, has been applied, drugs may help promote recovery.

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.