July 20, 2006 -- The US Food and Drug Administration (FDA) has approved a long-acting 68-mg etonogestrel implant for contraceptive use; and a new indication for rivastigmine tartrate capsules and oral solution allowing their use for the treatment of mild to moderate dementia associated with Parkinson's disease.

Single-Rod Etonogestrel Contraceptive Implant (Implanon) Effective for Up to 3 Years

On July 17, the FDA approved a long-acting 68-mg etonogestrel implant ( Implanon, made by Organon USA, Inc, a division of Akzo Nobel NV) for contraceptive use. The device is made of a soft biodegradable polymer often used in joint prostheses and is inserted subdermally on the inside of a woman's upper arm.

The matchstick-sized (2 x 40 mm; 0.08 x 1.5 in) single-rod implantable contraceptive is 99% effective for up to 3 years. It releases etonogestrel at a rate of 60 to 70 µg/day during weeks 5 and 6, after which the rate decreases to approximately 35 to 45 µg/day by the end of the first year, 30 to 40 µg/day at the end of the second year, and 25 to 30 µg/day at the end of year 3. At the end of the 3-year period, the device should be removed and may be replaced with a new implant if continued contraception is desired.

In women with no preceding hormonal contraceptive use, the device should be implanted between days 1 to 5 of the natural cycle; for those currently taking combination oral contraceptives, implantation should be performed on the day after taking the last active tablet in a given cycle, but no later than the last day of the tablet-free or placebo interval. Women currently taking progestin-only contraceptives may receive the implant at any time.

Use of an additional contraceptive method is advised during the first 7 days postimplantation. The implant can be removed at any time on patient request; according to a company news release, women then rapidly return to preimplantation fertility. The implant should also be removed in the event of pregnancy.

Women should be advised that use of the etonogestrel implant does not protect against HIV infection and other sexually transmitted diseases. As with any progestin-only contraceptive, use of the implant is associated with a risk for irregular bleeding that can occur at any time and present as increased or decreased bleeding frequency or duration, including amenorrhea. As with other hormonal contraceptives, headache, acne, dysmenorrhea, and emotional lability have also been reported.

In clinical studies, local implant-site complications occurred in 3.6% of patients and included inflammation, erythema, hematoma, and pain. The rate of complications leading to implant removal were also low (1.7%) and included impalpability of implant, broken or damaged implant, difficult localization, slight migration, and fibrosis.

Use of hormonal contraceptives is linked to increased risks for several serious adverse effects, including thromboembolic diseases. Because cigarette smoking increases the risk for serious cardiovascular adverse effects, women who use hormonal contraceptives (particularly those aged 25 years and older) are strongly advised not to smoke.

The 68-mg single-rod etonogestrel implant has been used by women in more than 30 countries since 1998. The company will be conducting a national clinical training program to train healthcare providers on proper implant insertion and removal techniques; participation is required to prescribe the device, which will be released in the United States later this year and become more widely available in 2007.

Rivastigmine Tartrate (Exelon) for Dementia of Parkinson's Disease

On June 27, the FDA approved a new indication for rivastigmine tartrate capsules and oral solution ( Exelon, made by Novartis Pharmaceuticals Corp), allowing their use for the treatment of mild to moderate dementia associated with Parkinson's disease (PD).

According to the FDA, an estimated 0.2% to 0.5% of individuals older than 65 years are affected by Parkinson's dementia and experience such symptoms as impairments in executive function, memory retrieval, and attention.

Although these symptoms are characteristic of Parkinson's dementia, a reliable diagnosis of the condition can also be made (without documentation of the aforementioned symptoms) in patients who experience a progressive dementia syndrome at least 2 years after a diagnosis of PD has been made and after other causes of dementia have been ruled out.

The approval was based on 24-week data from the large-scale, international, EXelon in PaRkinson's disEaSe dementia Study (EXPRESS) in 541 patients with Parkinson's-related dementia (mean age, 72.7 years; 35.1%, women) who were randomized in a 2:1 ratio to receive rivastigmine or placebo.

The study drug was initiated at a dose of 1.5 mg twice daily and then increased by 1.5 mg twice daily at intervals of 4 weeks or more to the highest tolerated dose for the remainder of the trial (range, 3 - 12 mg/day).

Results in 410 patients showed that rivastigmine therapy yielded significant improvements compared with placebo in terms of cognitive function and overall functioning, as evaluated using the Alzheimer's Disease Assessment Scale-cognition (ADAS-cog; +2.1 vs -0.7; P < .001) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change scale (ADCS-CGIC; 3.8 vs 4.3; P = .007).

Because patients receiving placebo showed a decline of nearly 1 point on the ADAS-cog scale during a 24-week period, an improvement of 2.1 points in the rivastigmine group may represent approximately 1 year's advantage.

In addition, specific tests for memory, attention, behavioral symptoms, and verbal fluency consistently showed significantly better outcomes for rivastigmine compared with placebo ( P < .05 for all).

Rivastigmine-related adverse events were mild to moderate in nature and most commonly included gastrointestinal effects, dyspepsia, and asthenia. Motor scale assessments showed that use of the drug did not cause overall worsening of Parkinsonian symptoms compared with baseline or placebo; mild to moderate tremor was reported but rarely led to discontinuation of treatment.

The FDA notes that gastrointestinal effects were dose related and consisted of nausea (47% vs placebo, 31%), vomiting (31% vs 6% overall), titration phase (24% vs 3%), and weight loss. In clinical trials, women were more likely than men to experience weight loss at rivastigmine doses greater than 9 mg/day (26% vs 18%).

Because of these effects, rivastigmine should always be initiated at a dose of 1.5 mg twice daily (3 mg/day) and then titrated in intervals of at least 4 weeks' duration to twice-daily doses of 3, 4.5, and 6 mg (corresponding to doses of 6, 9, and 12 mg/day) as tolerated.

In patients experiencing significant adverse events, treatment should be interrupted for several doses and then resumed at the same or next lower dose level. Treatment that is interrupted for longer than several days should be reinitiated at the lowest daily dose to reduce the risk for severe vomiting and potentially serious complications.

Rivastigmine was approved previously for this indication in the European Union, Switzerland, and several Latin American countries, including Brazil. It is also currently approved for the treatment of mild to moderate Alzheimer's dementia by the FDA and European Commission.

http://hcp.implanon.com/images/implanon_prescribinginfo_tcm624-170329.pdf