Newly approved drugs in 2003

December 2003

This month’s year-end column will review new anti-infective drugs approved by the FDA in 2003. Some products represent new dosage forms or new indications of drugs previously available, while another represents the first of a new class of antibacterial agents. Several products indicated for HIV infection were also approved in 2003, but will not be discussed in this month’s column: emtricitabine (Emtriva, Gilead Sciences), enfuvirtide (Fuzeon, Roche/Trimeris), fosamprenavir (Lexiva, GlaxoSmithKline), and atazanavir (Reyataz, Bristol-Myers Squibb).

Two other newly approved drugs with infectious disease treatment uses have been previously been described in the Pharmacology Consult column, FluMist (September 2003) and Alinia (treatment of giardiasis, July 2003).

Daptomycin

Perhaps the most interesting newly approved agent for 2003 is daptomycin. Daptomycin (Cubicin, Cubist) represents the first approved product of a new class of anti-infectives, cyclic lipopeptides. Daptomycin is indicated for the treatment of complicated skin and skin structure infections caused by Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp equisimilis and Enterococcus faecalis (vancomycin-susceptible strains only). Daptomycin has no activity toward gram-negative bacterial pathogens. Unfortunately, daptomycin is not approved for use in children younger than 18 years of age. Cyclic lipopeptides’ unique mechanism of action results from binding to bacterial membranes, with a resultant depolarization of membrane potential. This leads to protein, DNA and RNA synthesis inhibition and bacterial cell death.

Clinical studies that led to daptomycin’s FDA approval included two randomized, multicenter, single-blind trials comparing daptomycin to vancomycin or a semi-synthetic penicillin (eg, nafcillin) for the treatment of complicated skin and skin structure infections (infections of wound, abscess, cellulitis, ulcer) in adults. Clinical success rates did not differ among patients receiving daptomycin or the comparative antibiotic. Study patients infected with MRSA who were microbiologically evaluable also had similar treatment success rates: 21/28 (75%) and 25/36 (69.4%) for daptomycin and vancomycin, respectively (P values not given). The most commonly reported adverse effects of daptomycin therapy in clinical trials included constipation, nausea, injection site reactions and rash. An uncommon (2.8%) but unique adverse effect reported in these trials was an elevation of serum creatine phosphokinase (CPK). The package insert states that patients should be monitored for muscle pain or weakness (especially of the distal extremities) and CPK should be monitored weekly while receiving daptomycin, and therapy should be halted if CPK levels reach five-fold increases with symptoms of myopathy or 10-fold increases without symptoms. Most patients with daptomycin-induced CPK increases did not have related symptoms and CPK levels returned to normal upon therapy discontinuance. Thus, the availability of daptomycin represents another treatment option for complicated skin infections. The relatively few studies to date indicate it is equally effective as current therapies. Daptomycin’s unique pharmacologic mechanism may afford this agent usefulness for treating serious infections when the bacterial pathogens display resistance to current treatments, although considerable more study data need to be assessed to understand the clinical significance of this. While daptomycin appears to be generally well tolerated, its potential for a drug-induced myopathy requires careful monitoring. The cost of using daptomycin is likely higher than comparative drugs — about $135 for one day’s therapy — not including the additional laboratory monitoring for adverse effects.

Valacyclovir

Valacyclovir (Valtrex, GlaxoSmithKline) is not new to the commercial market, but it has received a new indication — suppression and reduction of heterosexual transmission of genital herpes in immunocompetent individuals. No other antiviral agent shares this indication, which is limited to the adult population. Approval by the FDA was based upon a double blind, placebo-controlled eight month trial (unpublished) of 1,484 monogamous, heterosexual adult couples (discordant for HSV-2 infection). All couples were counseled on safe sex practices and condom use. Symptomatic acquisition of HSV-2 in susceptible partners was the primary study endpoint; HSV-2 seroconversion in the susceptible partner was also evaluated. Overall HSV-2 acquisition (symptomatic and/or seroconversion) was 1.9% (14/743) and 3.6% (27/741) in the valacyclovir and placebo groups, respectively (P values not given). This equates to a 48% reduction in overall HSV-2 acquisition. Symptomatic HSV-2 acquisition was reduced by 75% (0.5% for valacyclovir vs. 2.2% for placebo). While the results of this study are encouraging, its limitations should be considered. Study patients were counseled on safe sex practices and use of a condom — how this non-drug therapy, while optimal, compares to “real-world” sexual practices and the implications for HSV-2 transmission reduction remain to be delineated. Additionally, study results may not be applicable to homosexual couples or individuals with multiple sexual partners.

DisperMox and Panixine

DisperMox and Panixine (both by Ranbaxy) represent new pharmaceutical dosage forms of currently available drugs – amoxicillin and cephalexin, respectively. These products are dispersible tablets and are mixed with two teaspoonfuls of water and then given to the patient (not stored). DisperMox is available in 200 mg and 400 mg strengths as a strawberry flavor. Panixine is available in 125 mg and 250 mg strengths as a fruity peppermint flavor. DisperMox and Panixine offer another dosage form choice to children, and advantages of their use may include children who do not tolerate (eg, taste) the suspension or chewable tablet dosage forms, or other circumstances where suspensions are not desired by caregivers (eg, when traveling from home). Because published taste tests of commonly used antibiotic suspensions reveal that cephalexin and amoxicillin rate generally well, taste may not be a major advantage that DisperMox or Panixine offer. Convenience may be an advantage.

Ciprofloxacin-dexamethasone

Ciprofloxacin-dexamethasone suspension (ciprofloxacin 0.3% and dexamethasone 0.1%, Ciprodex Otic, Alcon) is newly available for treating acute otitis media with tympanostomy tubes and otitis externa in ages 6 months and older. Several other products are used for these conditions (eg, Cortisporin, opthalmic antibiotic/corticosteroid products given in the ear), although ofloxacin otic and now ciprofloxacin-dexamethasone are the only products specifically approved by the FDA for use in middle ear disease in patients with tympanostomy tubes. In an unpublished randomized, controlled trial comparing ciprofloxacin-dexamethasone with ofloxacin otic in the treatment of acute otitis media with tympanostomy tubes, clinical cure rates were similar.

Both ciprofloxacin-dexamethasone and ofloxacin otic are dosed BID. Ciprofloxacin-hydrocortizone otic (Cipro HC otic, ciprofloxacin 0.2% and hydrocortisone 1%), also manufactured by Alcon, is currently commercially available and is indicated for otitis externa (ages 1 year and older). No published studies have directly compared ciprofloxacin-hydrocortizone with ciprofloxacin-dexamethasone. Both ciprofloxacin-hydrocortizone and ciprofloxacin-dexamethasone are approved for BID dosing, as compared with TID-QID dosing for Cortisporin. Because no studies have compared ciprofloxacin-hydrocortizone with ciprofloxacin-dexamethasone, it is not known if clinical differences exist among these products. Ciprofloxacin-dexamethasone does contain dexamethasone, a relatively more potent corticosteroid than hydrocortisone. It has been suggested that ciprofloxacin-dexamethasone is more effective when granulation tissue surrounds the tympanostomy tube(s). Costs of ofloxacin otic ($75, average wholesale price, AWP) and ciprofloxacin-hydrocortizone ($75, AWP) are higher than products available generically (eg, opthalmic gentamicin 0.3%, $8 AWP). The cost of ciprofloxacin-dexamethasone is likely to be similar to ofloxacin otic.

Moxifloxacin, gatifloxacin ophthalmic

Moxifloxacin (Vigamox, Alcon) ophthalmic and gatifloxacin (Zymar, Allergan) ophthalmic are new fluoroquinolone antibiotic ophthalmic solution products indicated for the treatment of bacterial conjunctivitis in ages 1 year and older. Moxifloxacin ophthalmic and gatifloxacin ophthalmic are fourth-generation fluoroquinolones with antimicrobial activity toward Haemophilus influenzae, S. pneumoniae and S. aureus, among other potential bacterial pathogens. Gatifloxacin’s approved dosing schedule includes one drop every two hours while awake on days one and two and QID dosing on days three through seven. Moxifloxacin is dosed as one drop TID for seven days. Numerous other products are currently available for the treatment of bacterial conjunctivitis, many as generic (and thus less costly) formulations. Antibiotics and classes available include erythromycin, aminoglycosides (gentamicin, tobramycin), bacitracin, sulfonamides, and combination products (eg, polymixin B+neomycin+bacitracin). Several products additionally contain corticosteroids. Other fluoroquinolone products include ciprofloxacin (Ciloxan, Alcon), norfloxacin (Chibroxin, Merck), ofloxacin (Ocuflox, Allergan), and levofloxacin (Quixin, Santen). While moxifloxacin and gatifloxacin are broader in their antibacterial spectrum as compared with currently available fluoroquinolone ophthalmic products, how this may translate into a clinical advantage, if at all, has yet to be determined. Cost may be an issue for consideration by clinicians, as several other broad-spectrum products are available generically (eg, polymixin B+neomycin+gramicidin). Several products are also available as ointments (eg, tobramycin, ciprofloxacin, others), which may be useful in some patients. As with the above otic products, newer opthalmic products have higher costs than products available generically – Ciloxin ($48, AWP), Quixin ($40, AWP), gentamicin generic ($8, AWP). Costs for moxifloxacin and gatifloxacin will likely be competitive to other ophthalmic fluoroquinolone products.

For more information:

• Cubist Pharmaceuticals. Product information – Cubicin. 2003.
• Campanaro ES. Comparison of efficacy and safety of daptomycin (DAP) vs. semisynthetic penicillin (SSP) and vancomycin (VAN) in patients with complicated skin and skin structure infections (cSSSIs). Poster L-737. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Sept. 14-17, 2003. Chicago.
• GlaxoSmithKline. Product information – Valtrex. 2003.
• Ranbaxy Laboratories Ltd. Product information – DisperMox, Panixine. 2003.
• Bell EA. Tastes of liquid medications: pediatric implications. The Journal of Pediatric Pharmacy Practice. 1999;4:43-50.
• Alcon Inc. Product information – Ciprodex. 2003
• Morden NE. Topical fluoroquinolones for eye and ear. Am Fam Physician. 2000;62:1870-1876.
• Alcon Inc. Product information – Vigamox. 2003.
• Dalhoff A. In vitro antibacterial activity and pharmacodynamics of new quinolones. European Journal of Clinical Microbiology and Infectious Diseases. 2003;22:203-221.
• Allergan Inc. Product information – Zymar. 2003.