This edition of Staying Well looks at new treatment options for menopause. The menopause is a single event in life: a woman's last menstrual period. The average age at menopause is 51.5 years, ranging from 45 to 55 years.[1]Because hormone therapy (estrogen alone after hysterectomy, or with progestin in presence of an intact uterus) is no longer recommended for prevention of chronic conditions, deciding who needs treatment is more personalized and individualized. The decision to treat is based on the presence and severity of menopausal symptoms, including hot flashes and dyspareunia. It also means matching the type of symptoms experienced by a woman with specific therapies, taking other current and past medical conditions into account.Two new selective estrogen receptor modulators (SERMs) and an old depression medication (in a new dose) are changing the landscape of menopause treatment options.[2-4] Here is a discussion of the newest kids on the block.
 

Vasomotor Symptoms: Feeling Hot, Hot, Hot?
For some women, the menopause transition is a breeze. It's merely a blip on the radar screen. For others, it is an unending inferno. Hot flashes occur in 75% of women after menopause.[5] Ten years after their last natural menstrual period (menopause), 10% of women still experience vasomotor symptoms. For some women, symptoms last even longer. Up to 16% of women aged 85 years or older still experience vasomotor symptoms.[1]

"Hormone-Free" Hot Flash Relief
For women who want hot flash relief without taking hormones, paroxetine (Brisdelle®) may be the ticket. Yes, this is the same drug that is already approved by the US Food and Drug Administration (FDA) for treating depression, anxiety, and obsessive-compulsive disorder, but the dose is different. On June 28, 2013, a lower dose of paroxetine -- 7.5 mg, taken at bedtime -- was FDA-approved to treat moderate to severe hot flashes.[5]Safety and efficacy were established by 2 randomized, double-blind, placebo-controlled trials including more than 1100 symptomatic women with documented symptom improvement at 12 and 24 weeks. Of note, the mechanism of action is unknown.[5]
 
Because this hot flash treatment contains no estrogen, you might think it would be safe to give to women who have, or have had, breast cancer. Not necessarily. Heed this additional labeled warning of drug/drug interaction: Paroxetine strongly inhibits the cytochrome P450 CYP2D6 enzyme, the same enzyme that converts tamoxifen to its metabolite endoxifen, a main contributor to its pharmacologic activity. Paroxetine thus reduces the effectiveness of tamoxifen, so don't prescribe it to women taking tamoxifen. Other warnings include increased bleeding risk and risk for serotonin syndrome.[2,5,6]
 
A black box warning about suicidality is also included on the label -- just as on other paroxetine preparations. This warning is probably the reason that the FDA advisory committee voted 10-4 against approval for treating menopausal symptoms. Noting that the drug provided a hormone-free option to treat hot flashes, the FDA overruled the advisory committee's opinion and approved this treatment.[2,5,6]
 

Hot Flash Relief With Bone Help
In October 2013, the FDA approved a combination of conjugated estrogen (0.45 mg) with bazedoxifene (Duavee®; 20 mg) for prevention of osteoporosis and treatment of moderate to severe vasomotor symptoms.[3,7]A clinical trial known as SMART (Selective Estrogens, Menopause, And Response to Therapy) demonstrated a 74% reduction in moderate to severe hot flashes at 12 weeks. Clinical trials described in the package insert showed significantly increased bone density at the hip and lumbar spine compared with reductions in bone density seen in patients receiving placebo.[7]
 
This dual agent was developed by Wyeth (remember Premarin®, a conjugated equine estrogen derived from pregnant horse urine?) and is now owned by Pfizer. Although the label has taken "equine" off of the ingredient list, it does source the conjugated estrogen as being derived from the urine of pregnant horses. Bazedoxifene is a SERM with both estrogen-agonist effects (bone) and -antagonist effects (endometrium). This antagonistic effect on the endometrium prevents estrogen-associated endometrial hyperplasia, which can lead to uterine cancer. Thus, bazedoxifene provides an alternative to progestin that is protective of the endometrial lining.[3,7]
 
The combination drug is indicated only for women who have a uterus. Any vaginal bleeding in patients taking this medication must be evaluated. Warnings in the package insert discourage taking additional estrogens, progestins, or estrogen agonist/antagonists in addition to this combination drug.[3]There are some drug (and juice!) interactions that you need to be aware of. Concomitant use with CYP3A4 inhibitors, including erythromycin, clarithromycin, ketoconazole, itraconazole, and ritonavir, and also grapefruit juice, lessens the drug's protective effect by increasing estrogen exposure; this could increase risk for endometrial hyperplasia.[7] The package insert says this combination should not be used by women with blood clots or a history of blood clots, liver problems, breast cancer, or uterine cancer.[7]
 

Bye Bye, Dyspareunia: Sex and a New SERM
Some members of the media have called ospemifene (Osphena™) "the new female Viagra."[8] Although it has no mechanism for enhancing sexual arousal, ospemifene most certainly can make sex less painful and more comfortable (and therefore more desirable and enjoyable). How coincidental that ospemifene was FDA-approved in February (close to Valentine's Day) 2013 to treat moderate to severe dyspareunia owing to menopause-related vulvar and vaginal atrophy.[4,9]FDA approval was based on 3 placebo-controlled studies of more than 1800 postmenopausal women. Two of the trials showed statistically significant symptom improvement after 12 weeks of therapy, with the third trial supporting long-term safety.[9]
 
With declining estrogen level, the vaginal lining thins, becoming more dry, fragile, and friable. Although FDA-approved vaginal estrogen creams and vaginal estrogen suppositories are effective, they require application. This new treatment choice is a 60-mg pill that is taken orally once a day (with food).[9]Ospemifene has an estrogen agonist effect on vaginal and vulvar tissue as its mechanism of action. SERMs can also have estrogen-like effects on the endometrial lining, which lead to endometrial hyperplasia and can predispose to endometrial cancer. The FDA-mandated black box warning on the label is both concerning and confusing.[4]

Osphena is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, Osphena has estrogen agonistic effects. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. [See Warnings and Precautions (5.2)]

The warning states that ospemifene has estrogen-agonist effects on the lining of the uterus. It reminds users that adding progestin to estrogen reduces the risk for endometrial hyperplasia and refers to the warnings and precautions section of the label (section 5.2), which reiterates these points and then states combining progestin with ospemifene therapy was not evaluated in the clinical trials and any abnormal genital bleeding should be evaluated (with endometrial sampling).[4]
Even I am confused, and I am not alone. Does this mean that a woman with an intact uterus taking ospemifene should also take a progestin? The package insert wording is not clear.
The Medical Letter recommended that a woman with an intact uterus who takes ospemifene should also take a progestin.[9] After receiving multiple reader objections, the Medical Letter issued an addendum on October 14, 2013.[10] The addendum clarified that in ospemifene clinical trials, at 1 year, there were no cases of endometrial cancer (although not many women took the drug longer than 12 weeks). The amended recommendation states:

For now, it would not be unreasonable for postmenopausal women with an intact uterus who can be followed closely for vaginal bleeding or spotting and do not have risk factors for endometrial cancer (obesity hypertension, diabetes, nulliparity) to take ospemifene without a progestin. For all others, a progestin should be considered.

The black box warning on the label clearly warns of increased incidence rates of hemorrhagic stroke and venous thrombosis (1.45 per 1000 women), but these are low compared with those seen with estrogen-only therapy. There is another downside: hot flashes and excessive sweating. Therefore, this drug may not be best for women already suffering vasomotor symptoms.[4]
 

Seniors and Sex
Seniors are not only interested in sex; they're having it. In 2007, a New England Journal of Medicine [11] study looking at sexuality found that 73% of people aged 57-64, 53% of those aged 65-74, and 26% of those aged 75-84 reported sexual activity.
But as Dr. Emanuel Ezekiel pointed out in a recent New York Times editorial,[12] seniors are not necessarily having sex safely, citing surprising new data showing increases in sexually transmitted infections (STIs) in the over-65 age groups -- a 31% increase in chlamydia, and a 52% increase in syphilis. A study published in Annals of Internal Medicine documented higher rates of STIs, including HIV, in men taking erectile dysfunction drugs. Men aged 50 years or older who used erectile dysfunction drugs were 6 times less likely to use condoms and 5 times less likely to get tested for HIV than were men in their 20s.[13]
Comfort and stamina are not the only things with which our patients need help. Sex education, including "STI 101" information, is clearly in order.
 

Heads Up: New Toolkit for Practitioners
Here's a heads-up about a new menopause toolkit, developed by researchers in Australia and endorsed by the International Menopause Society.[1] The toolkit includes basic information (including definitions of pre-, peri-, and postmenopause), as well as decision tree algorithms to help direct therapy regimens. Some of the sections would make good reading for women undergoing this transition. The toolkit summarizes several core recommendations derived from the 2013 Global Consensus Statement on Menopausal Hormone Therapy (Table).
Table. Menopause Toolkit Highlights[1]

Health Concern

Recommendation

Vasomotor symptoms

Hormone therapy is the most effective therapy for vasomotor symptoms. Benefits often outweigh the risks for women younger than 60 years or if taken within 10 years after the start of menopause.

Use of progestins

Women with a uterus need endometrial protection with progestin. Women without a uterus should receive estrogen only.

Premature menopause (premature ovarian insufficiency)

Treat with hormone therapy to age of natural menopause -- at least.

Risk for VTE

Transdermal estrogen therapy is preferred over oral therapy for women at increased risk for VTE, including those who smoke and/or are obese. Oral estrogen is linked to higher risk for VTE compared with transdermal estrogen therapy.

Women with breast cancer

Hormone therapy should not be given to patients with breast cancer.

Bone protection

Hormone therapy protects against bone loss and fracture in women up to age 60 years and within 10 years of menopause.

VTE = venous thromboembolic disease
The toolkit recommends against compounded hormone preparations. The authors have a negative take on dehydroepiandrosterone (DHEA), stating that oral DHEA does not work for treating vasomotor symptoms or menopause-related mood changes or sexual dysfunction. Their stance on testosterone is somewhat supportive, stating, "In appropriate doses, testosterone may help improve sexual desire and arousal." However, this is a European-derived document. In the United States, no testosterone pills, creams, gels, or patches are currently FDA-approved for use in women.
The toolkit suggests tibolone as an alternative to estrogen/progestin therapy. Tibolone metabolites have estrogenic (protects bone, helps hot flashes, and helps vaginal tissue), progestogenic (on uterus), and androgenic (lowers high-density lipoprotein cholesterol) actions. Although tibolone is available in many countries throughout the world, it is not FDA-approved for use in the United States. The toolkit does discuss the FDA-approved bazedoxifene/estrogen combination and ospemifene but does not include mention of paroxetine.[1]
 

Final Thoughts
For treating hot flashes, we now have 2 new FDA-approved choices:
• Estrogen with a twist: the SERM bazedoxifene/conjugated estrogen (if uterus intact), no progestin needed;[2] and
• Paroxetine: for hormone-free relief (do not use in patients on tamoxifen).[3]
For treating vaginal/vulvar atrophy and dyspareunia, we now have a new FDA-approved oral alternative: ospemifene (but beware of causing more hot flashes), plus perhaps a progestin in women with an intact uterus.
It's not that estrogen and progestin are "out." It's simply that to prevent chronic diseases, we no longer treat menopause with hormones.[14] If hormones are necessary, use the smallest dose that relieves symptoms for the shortest period of time.[15]
There are new options for managing symptoms that take into account patient preference and the presence of other medical conditions. Consider all these therapies as you help women who are "transitioning" to stay cool, happy, and healthy!
BY:  Sandra Adamson Fryhofer, MD

Adjunct Associate Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia; Past President, American College of Physicians

References

1. Jane FM, Davis SR. A practitioner's toolkit for managing the menopause. Climacteric. 2014;17:1-16.
2. Noven Therapeutics, LLC. Brisdelle prescribing information. July 2013. http://www.brisdelle.com/brisdelle-pdf/Full-Prescribing-Information.pdf Accessed July 28, 2014.
3. Wyeth Pharmaceuticals, Inc. Duavee prescribing information. October 2013. http://labeling.pfizer.com/ShowLabeling.aspx?id=1174 Accessed July 28, 2014.
4. Penn Pharmaceuticals Services, Inc. Osphena prescribing information. February 2013. http://www.shionogi.com/pdf/PI/Osphena-PI.pdf Accessed July 28, 2014.
5. US Food and Drug Administration. FDA News Release. FDA approves the first non-hormonal treatment for hot flashes associated with menopause. June 28, 2013. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm359030.htm Accessed July 28, 2014.
6. Orleans RJ, Li L, Kim MJ, Sobhan M, Soule L, Joffe HV. FDA approval of paroxetine for menopausal hot flushes. N Engl J Med. 2014;370;1777-1779. Abstract
7. US Food and Drug Administration. Drugs. FDA approves Duavee to treat hot flashes and prevent osteoporosis. October 3, 2013. http://www.fda.gov/drugs/newsevents/ucm370679.htm Accessed July 28, 2014.
8. Gunter J. Is Osphena the new female Viagra? KevinMD. August 13, 2013. http://www.kevinmd.com/blog/2013/08/osphena-female-viagra.html Accessed July 28, 2014.
9. Ospemifene (Osphena) for dyspareunia. Med Lett Drugs Ther. 2013;55:55-56. http://secure.medicalletter.org/cannotaccess?ac=1&a=1420c&t=article&n=11884&p=tml&title=Ospemifene%20(Osphena)%20for%20Dyspareunia&i=1420 Accessed July 28, 2014.
10. Addendum: ospemifene (Osphena) for dyspareunia. Med Lett Drugs Ther. 2013;55:84. http://secure.medicalletter.org/cannotaccess?ac=0&a=1427d&t=article&n=11964&p=tml&

    title=Addendum:%20Ospemifene%20(Osphena)%20for%20Dyspareunia&i=1427

    Accessed July 28, 2014.
11. Lindau ST, Schumm LP, Laumann EO, Levinson W, O'Muircheartaigh CA, Waite LJ. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007;357:762-774. Abstract
12. Ezekiel EJ. Sex and the single senior. New York Times. January 18, 2014. http://www.nytimes.com/2014/01/19/opinion/sunday/emanuel-sex-and-the-single-senior.html?_r=0 Accessed July 28, 2014.
13. Jena AB, Goldman DP, Kamdar A, Lakdawalla DN, Lu Y. Sexually transmitted diseases among users of erectile dysfunction drugs: analysis of claims data. Ann Intern Med. 2010;153:1-7. Abstract
14. Moyer VA; US Preventive Services Task Force. Menopausal hormone therapy for the primary prevention of chronic conditions: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2013; 158:47-54. Abstract
15. US Food and Drug Administration. Menopause and hormones: common questions. http://www.fda.gov/forconsumers/byaudience/forwomen/ucm118624.htm Accessed July 28, 2014.

Medscape Internal Medicine © 2014  WebMD, LLC
Cite this article: Hot Tips for Menopausal Hot Flashes. Medscape. Aug 12, 2014.