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.

The pathogenesis of acne is multifactorial: follicular hyperkeratinization, bacteria, sebum production, androgens, and inflammation all play a role. The gram-positive microaerophilic bacteria Propionibacterium acnes promotes development of acne lesions by secreting chemotactic factors that attract leukocytes to the follicle, causing inflammation.

The FDA has approved Technivie (Abbvie), a fixed-dose combination of the direct-acting antiviral agents ombitasvir and paritaprevir and the pharmacokinetic enhancer ritonavir, for oral treatment of chronic hepatitis C virus (HCV) genotype 4 infection in patients without cirrhosis. It is indicated for use in combination with ribavirin. Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir, an HCV RNA polymerase inhibitor that has little activity against HCV genotype 4, is approved as Viekira Pak for treatment of HCV genotype 1 infection.1

HCV genotype 4 is uncommon in the US and Canada. It is the most prevalent strain of HCV in Central sub-Saharan Africa, North Africa, and the Middle East.2 Technivie plus ribavirin was the first all-oral treatment approved for treatment of HCV genotype 4. Ledipasvir/sofosbuvir (Harvoni)3 was also recently approved for this indication; it does not require coadministration with ribavirin and can be used in patients with or without cirrhosis. Its use for this and other new indications will be reviewed in a future issue.

FDA approval of Technivie was based on an open-label trial (PEARL-I) in 86 treatment-naive and 49 treatment-experienced non-cirrhotic patients with HCV genotype 4 infection. Treatment-naive patients were randomized to receive Technivie with or without ribavirin for 12 weeks; all treatment-experienced patients received the combination plus ribavirin for 12 weeks. The rate of sustained virologic response 12 weeks after stopping treatment (SVR12), the primary endpoint, was 91% (40/44) in treatment-naive patients not receiving ribavirin and was 100% in both treatment-naive (42/42) and treatment-experienced (49/49) patients receiving the combination plus ribavirin.4

Adverse effects observed with Technivie in the clinical trial included asthenia, fatigue, nausea, insomnia, pruritus, and skin reactions. Like Viekira Pak, Technivie has been associated with serious, sometimes fatal cases of hepatic decompensation and is contraindicated in patients with moderate to severe (Child-Pugh B/C) hepatic impairment.5 It is also contraindicated in patients taking ethinyl estradiol (because of a risk of ALT elevation), CYP3A4 inducers such as rifampin, or certain sensitive CYP3A4 substrates such as midazolam or simvastatin.6

Each Technivie tablet contains 12.5 mg of ombitasvir, 75 mg of paritaprevir, and 50 mg of ritonavir. The recommended dosage is two tablets taken once daily in the morning with a meal for 12 weeks. Ribavirin should be coadministered with Technivie at a daily dose of 1000 mg in patients weighing <75 kg or 1200 mg in those weighing ≥75 kg. Use of Technivie alone may be considered in treatment-naive patients who cannot take or tolerate ribavirin. A 12-week supply of Technivie costs $76,653.7

1. A 4-drug combination (Viekira Pak) for hepatitis C. Med Lett Drugs Ther 2015; 57:15.
2. JP Messina et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 2015; 61:77.
3. A combination of ledipasvir plus sofosbuvir (Harvoni) for hepatitis C. Med Lett Drugs Ther 2014; 56:11.
4. C Hézode et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet 2015; 385:2502.
5. In brief: hepatic injury with hepatitis C drugs. Med Lett Drugs Ther 2015; 57:156.
6. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med Lett Drugs Ther 2013; 55:e44.
7. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer's published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. November 5, 2015. Reprinted with permission by First Databank, Inc. All rights reserved. ©2015 www.fdbhealth.com/policies/drug-pricing-policy.

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Implants, intrauterine devices (IUDs), and sterilization are the most effective contraceptive methods available. Pills, patches, rings, and injectables, when used correctly, are also highly effective in preventing pregnancy. Barrier and fertility-based methods have the highest rates of failure.

The FDA has approved Viekira Pak (Abbvie), a fixed-dose combination of two new direct-acting antiviral agents (ombitasvir, paritaprevir) with the pharmacologic enhancer ritonavir in one tablet, co-packaged with a third new direct-acting antiviral agent (dasabuvir) in a second tablet, for oral treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Genotype 1 is responsible for 70-80% of HCV infections in the US.

The FDA has approved miltefosine (Impavido – Knight Therapeutics), an oral alkylphosphocholine analog, for treatment of visceral, cutaneous, and mucosal leishmaniasis caused by some Leishmania species. It is the first drug to be approved by the FDA for treatment of cutaneous and mucosal leishmaniasis and the first oral drug to be approved for treatment of visceral leishmaniasis.

Perampanel (per am’ pa nel; Fycompa – Eisai), a first-in-class noncompetitive AMPA receptor antagonist, has been approved by the FDA for adjunctive treatment of partial-onset seizures in patients ≥12 years old. New drugs for epilepsy are often initially approved by the FDA as adjunctive treatment for partial seizures.

The FDA has approved a once-daily extended-release (ER) formulation of the antiepileptic topiramate (Trokendi XR – Supernus) for initial monotherapy in patients ≥10 years old with partial onset seizures or primary generalized tonic-clonic seizures and for adjunctive therapy in patients ≥6 years old with partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome. Topiramate has been available for many years as an immediate-release (IR) formulation (Topamax, and generics) for the same indications in patients ≥2 years old

The FDA has approved Quartette (Teva), an extended-cycle combination oral contraceptive containing increasing doses of the estrogen ethinyl estradiol (EE) combined with the progestin levonorgestrel (LNG). The rationale is that a gradual increase in the EE dose may reduce unscheduled bleeding or spotting, a common adverse effect of extended-cycle oral contraceptives.

The FDA recently approved Skyla (Bayer), the first new intrauterine device (IUD) in the US in 12 years. It releases levonorgestrel, a synthetic progestin, over a period of 3 years. A table summarizing contraceptive methods available in the US appears on page 22.

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 pathogenesis of acne is multifactorial: follicular hyperkeratinization, bacteria, sebum production, androgens, and inflammation all play a role. The gram-positive microaerophilic bacteria Propionibacterium acnes promote development of acne lesions by secreting chemotactic factors that attract leukocytes to the follicle, causing inflammation.

The FDA has announced that combination hormonal contraceptives (CHCs) containing the synthetic progestin drospirenone (Yaz, Yasmin, Beyaz, Safyral, and others) may be associated with a higher risk of thromboembolism than CHCs containing other progestins.1

The new warning was based partly on an unpublished, FDA-funded, retrospective study that found a 1.7-times higher risk of venous thromboembolism among US women who used a CHC that contained drospirenone than among women whose CHC contained levonorgestrel, norgestimate or norethindrone as the progestin component.2 As with all retrospective studies, unknowable confounding factors, such as why doctors prescribed one progestin over the other, could have distorted the results.

All CHCs increase the risk of venous thromboembolism; whether the progestin component affects the risk has been controversial. The Medical Letter and several other reviews and consensus statements have found no convincing evidence of an increased risk with drospirenone.3-5

1. FDA Drug Safety Communication: Updated information about the risk of blood clots in women taking birth control pills containing drospirenone. Available at www.fda.gov/Drugs/DrugSafety/ucm299305.htm. Accessed April 23, 2012.

2. FDA. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. Available at www.fda.gov/downloads/Drugs/DrugSafety/ucm277384. Accessed April 23, 2012.

3. Combination oral contraceptives and the risk of venous thromboembolism. Med Lett Drugs Ther 2010; 52:23.

4. RL Reid. Oral contraceptives and venous thromboembolism: pill scares and public health. J Obstet Gynaecol Can 2011; 33:1150.

5. L Manzoli et al. Oral contraceptives and venous thromboembolism: a systematic review and meta-analysis. Drug Saf 2012; 35: 191.

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Six years after an FDA advisory committee recommended development of a combination tablet containing an oral contraceptive and folic acid,1 the FDA has approved Beyaz (Bayer), a combination of the oral contraceptive Yaz2 with 451 mcg of levomefolate calcium, the primary metabolite of folic acid.3 According to the FDA, an unpublished double-blind, randomized U.S. trial in 379 healthy women 18-40 years old found that the combination increased serum folate levels. In an unpublished German study using a similar oral contraceptive/ levomefolate combination (summarized in the package insert), folate levels remained elevated for several weeks after levomefolate was stopped.4

The standard US diet provides 50-500 mcg of absorbable folate per day, but the bioavailability of folate in mixed diets varies. Folic acid in supplements is more bioavailable than folate in food.5 Supplementing the diet of women of childbearing age with 400 mcg of folic acid per day, the amount contained in most multivitamin preparations, has dramatically decreased the incidence of neural tube defects in their offspring.To effectively prevent neural tube defects, folic acid supplementation should be started at least one month before conception and continued through the first 2-3 months of pregnancy. Since incorrect or inconsistent use of oral contraceptives may account for as many as one million pregnancies in the US each year, all women capable of becoming pregnant should take a folic acid supplement.6,7

1. Folic acid supplementation to prevent neural tube defects. Med Lett Drugs Ther 2004; 46:17.

2. Three new oral contraceptives. Med Lett Drugs Ther 2006; 48:77.

3. Choice of contraceptives. Treat Guidel Med Lett 2010; 8:89.

4. FDA approves combination contraceptive containing a folate. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm227237.htm. Accessed October 5, 2010.

5. GP Oakley, Jr. Eat right and take a multivitamin. N Engl J Med 1998; 338:1060.

6. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009; 150:626.

7. AM Kaunitz. Oral contraceptive use, pregnancy intendedness and folic acid intake. FDA Advisory Committee for Reproductive Health Drugs meeting; December 15, 2003; Gaithersburg, MD. Available at http://www.fda.gov/ohrms/dockets/ac/03/transcripts/4002T1.DOC. Accessed November 3, 2010.

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The choice of which contraceptive to use may vary from one stage of reproductive life to another. Intrauterine devices (IUDs), progestin implants and sterilization are the most effective contraceptive methods available to women. Hormonal contraceptives, when used correctly, are also highly effective in preventing pregnancy. Barrier and fertility-based methods have the highest rate of failure.

The FDA has approved the marketing of Natazia (Bayer), a 4-phase oral contraceptive containing the estrogen estradiol valerate and the progestin dienogest, both used for the first time in the US for this indication.

Combination oral contraceptives increase the risk of venous thromboembolism (VTE). Their benefits, in addition to preventing pregnancy, include lowering the risk of ovarian and endometrial cancer, reducing dysfunctional uterine bleeding and increasing serum hemoglobin concentrations. Are these benefits worth the risk? And are some combination oral contraceptives safer than others?

The pathogenesis of acne is multifactorial: follicular hyperkeratinization, bacteria, sebum production, androgens and inflammation all play a role. The gram-positive microaerophilic bacteria Propionibacterium acnes promote development of acne lesions by secreting chemotactic factors that attract leukocytes to the follicle, causing inflammation.

Transdermal, transvaginal and intrauterine hormone delivery systems have made highly effective contraceptive products more convenient to use. New oral contraceptive options include regimens with fewer or shorter hormone-free intervals.

Lybrel (Wyeth) is the first FDA-approved low-dose combination oral contraceptive taken 365 days a year without a placebo or pill-free interval. All tablets contain low doses of levonorgestrel (0.09 mg) and ethinyl estradiol (20 mcg). Most oral contraceptives are packaged as a 21/7 cycle (21 days of active tablets and 7 days of placebo), resulting in 13 withdrawal bleeding episodes each year. Two formulations are taken for 24 days followed by 4 days of inert tablets (Yaz and Loestrin 24). Two others (Seasonique and Seasonale) have a 91-day cycle with only 4 withdrawal bleeds per year.

Femcon Fe (Warner Chilcott) is being advertised as the world's only chewable oral contraceptive. It was formerly marketed as Ovcon 35 Fe. Each packet provides 21 tablets containing 0.4 mg norethindrone and 35 mcg ethinyl estradiol, and 7 tablets with only 75 mg of ferrous fumarate. Femcon Fe has the same active hormonal ingredients as Ovcon 35 (Warner Chilcott), which has been available since 1976, and its generic equivalent Balziva (Barr); neither formulation contains iron. The spearmint-flavored Femcon Fe pill can be chewed or swallowed whole. According to the package labeling, if the pill is chewed, it should be followed by a full glass of water. The generic equivalent is not chewable, but it costs about 15 cents less per pill, and presumably comes with a lower co-pay in most insurance plans. Download U.S. English

The pathogenesis of acne is multifactorial: follicular hyperkeratinization, Propionibacterium acnes bacteria, sebum production, androgens and inflammation have all been implicated. P. acnes, a gram-positive microaerophilic bacterium, plays an important role in the development of acne lesions by secreting chemotactic factors that attract leukocytes to the follicle, causing inflammation.

Estrogen is the most effective treatment for menopausal vasomotor symptoms (hot flashes), but the Women's Health Initiative study found that women who took estrogen plus a progestin for more than 5 years were at increased risk for myocardial infarction, stroke, pulmonary emboli, deep vein thrombosis, breast cancer, and possibly dementia. Are there effective alternatives?

In recent years, several new contraceptive options have become available in the United States. Novel hormone delivery systems such as transdermal, transvaginal and intrauterine devices have improved the convenience of highly effective contraceptive products. Like oral contraceptives and most barrier contraceptives, these devices do not protect against sexually transmitted diseases.

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).

Seasonale (Barr), the first "extended-cycle" oral contraceptive, is now available in the US for pregnancy prevention. Active tablets containing 30 ╡g of ethinyl estradiol and 0.15 mg of levonorgestrel are taken for 84 consecutive days, followed by 7 days of inactive tablets, allowing for withdrawal bleeding only four times a year. Other combination oral contraceptives are dispensed as 21 days of active tablets and 7 days of placebo or no tablets, resulting in 13 withdrawal bleeding episodes each year.

Even though its effectiveness has not been established, many patients take St. John's Wort (Hypericum perforatum), an over-the-counter herbal extract, to treat symptoms of depression, often without the knowledge of their physicians. Recent reports indicate that St. John's wort interacts adversely with a number of drugs.

Two types of oral contraceptives are available in the USA: combination oral contraceptives that contain both an estrogen and a progestin, and progestin-only contraceptives, or "mini-pills."Used as directed, all oral contraceptives marketed in the USA are similarly effective in preventing pregnancy.