Vasomotor symptoms of hot flashes, hot flushes, and night sweats are probably best known as being associated with female menopause. These vasomotor symptoms affect an estimated 75% of women aged over 50 years. However, these vasomotor symptoms may also be experienced, for example, by women undergoing breast cancer treatment with the anti-estrogen drug tamoxifen, by women who have had pituitary failure and do not secrete luteinizing hormone and follicular stimulating hormone, and by men who are undergoing androgen deprivation therapy following a bilateral orchiectomy or treatment with gonadotrophin-releasing-hormone agonist for metastatic prostate cancer.
Hot flashes are manifested as an increase in skin temperature, and are often accompanied by a sudden onset of sweating on the face, neck and chest. Hot flashes significantly affect the quality of life for those who experience them, and are particularly bothersome at night as they can disturb sleep, leading to fatigue and lack of productivity during the day. While hot flashes are commonly associated with females in a perimenopausal or menopausal state of life, they are not, however, unique to menopause. Hot flashes can be caused by a variety of conditions, including thyroid disease, infection, epilepsy, insulinoma, carcinoid syndromes, leukemia, pulmonary tuberculosis, pancreatic tumors, autoimmune disorders, and mast cell disorders. Hot flashes may occur in women diagnosed with cancer or other diseases treated by chemotherapy, wherein there is a temporary or permanent side effect on the ovaries. Hot flashes generally last several minutes and are evidenced by a visible flushing of the skin. Often dizziness, palpitations and diaphoresis accompany a hot flash episode.
Currently, a preferred treatment for hot flashes in patients is hormone replacement therapy either using estrogen and progesterone or estrogen-replacement therapy. Unfortunately, these hormone therapies are inappropriate for patients previously diagnosed with breast cancer, as either estrogen or progesterone may be associated with an increased risk of cancer recurrence and are known to specifically promote growth of breast cancer cell with estrogen receptors. Estrogen may also increase the risk of coronary and thromboembolic events during the first year of treatment. Although the use of low dose estradiol therapy may diminish the risk for these large specialized patient populations, the risks of estrogen therapy are still great.
There are numerous non-hormonal remedies commonly used by women suffering hot flashes including, for example, isoflavone, black cohosh, vitamin E, and the antidepressants fluoxetine, paroxetine, and venlafaxine. However, efficacy of these remedies is less than that of the hormone replacement therapies.
The gamma-aminobutyric acid (GABA) analog gabapentin is approved in the United States for use in treating epilepsy and post-herpetic neuralgia, in immediate-release tablets and capsules. The drug administered in immediate release dosage forms is also being studied for use in reducing both the frequency and severity of hot flashes (Butt D. A. et al., Menopause, 2008:15(2):310-318; Reddy S. Y. et al., Obstetrics & Gyn., 2006:108(1):41-48; Pandya K. J. et al., Lancet, 2005:366(9488):818-824; Loprinzi C. L. et al., J. Clin. Oncology, 2007:25(3):308-312; U.S. Pat. No. 6,310,098).
When used in studies to assess effectiveness in the treatment of hot flashes, immediate release gabapentin forms require administration three times per day (t.i.d.), and result in undesired side effects. Side effects reported from use of immediate release gabapentin products include, most commonly, somnolence and dizziness, and to a lesser degree, fatigue, ataxia, weight gain, peripheral edema, diarrhea, headache, dry mouth, and blurred vision. More recently, gabapentin use has been associated with the serious side effect of reversible visual field constriction (Bekkelund et al., Brit Med. J 323:1193 (2006)). In studies involving use of gabapentin to treat menopausal symptoms, the prevalence of somnolence and dizziness side effects resulted in many women discontinuing use of the drug.
The need for t.i.d. dosing and unwanted side effects associated with immediate release gabapentin dosage forms may contribute to poor compliance for some patients in need of relief from vasomotor symptoms. The above described side effects in this generally healthy population can be a considerable barrier to compliance with gabapentin therapy. In this respect, controlled release dosage forms that would lower the number of daily dosings of gabapentin to once-daily (qd) or twice-daily (b.i.d.) dosings, particularly without a mid-day dose, would provide significant advantage over the conventional immediate release dosage forms.
The need for t.i.d. dosing is due partially to the fact that there is a decrease in bioavailability with increasing dose of the immediate release dosage form of gabapentin. This is attributed to partially carrier-mediated absorption (Stewart et al., Pharmaceutical Research, 1993, 10(2):276-281; Bourgeois, Epliepsia, 36 (Suppl. 5):S1-S7 (1995); Gram, Epliepsia, 37 (Suppl. 6):S12-S16 (1996); Drugs of Today, 31:613-9:975-82 (1995); Neurology, 44(Suppl. 5): S17-S32 (2003)). Overcoming poor bioavailability properties requires sustained exposure of the small intestine to gabapentin. Sustained-release formulations of gabapentin that provide prolonged exposure to the small intestine have successfully been formulated as gastric retentive dosage forms. These dosage forms are illustrated, for example, in U.S. Pat. Nos. 6,723,340 and 7,438,927, and U.S. Patent Publication Nos. 2003/0091630, 2003/0200611, and 2007/0184104. Gastric retentive dosage forms as described in these patents and patent publications are formulated to be retained in the stomach when taken with food, i.e., in a fed mode. Gastric retention is achieved either through the imbibition of fluid and resultant swelling upon administration or through design of a dosage form that has a size, prior to administration, which is sufficient for gastric retention in a fed mode. As a result, the gabapentin is slowly released in the stomach over time, upstream of the small intestine where gabapentin absorption is maximal.
Despite slow release of gabapentin, minimization of intolerable side effects of gabapentin requires that doctors titrate patients slowly to a maintenance dose. This titration period can take weeks or even a month. The complexity and length of the titration regimen may result in prematurely discontinuing therapy by patients prior to reaching the maintenance dose or to doctors preferring other therapeutic options.
In order for gabapentin and other GABA analogs, in particular pregabalin, to gain widespread acceptance for use to treat vasomotor symptoms due to diverse causes, and particularly due to hormonal changes before and during menopause, there is a need for a dosing regimen that facilitates patient compliance and reduces and/or eliminates adverse side effects. Treatment methods effective in ameliorating, preventing or attenuating vasomotor symptoms are needed, particularly for subjects contraindicated for other accepted treatments, such as hormone replacement therapy and estrogen replacement therapy, or who do not wish to take on the risks associated with these treatments.
USPTO Backgrounds
USPTO Backgrounds