Megace (megestrol) is a synthetic derivative of naturally occurring progesterone, which is used to increase appetite and weight gain in AIDS patients, and palliatively treat breast and endometrial cancer. Its mechanism of action is unknown. Megestrol may increase appetite by inhibiting the production of IL-6 and other pro-inflammatory cytokines. Although megestrol is indicated for AIDS patients, physicians have prescribed megestrol for the elderly population in hopes of increasing their appetite, protein stores, and quality of life.

In the elderly population, megestrol is found to be effective as an appetite stimulant. In a study by Yeh et al, geriatric patients were given megestrol 800 mg daily and reported an increase in weight gain and an enhanced quality of life. However, the study was short (12 weeks). Long-term use of megestrol had been associated with adrenal suppression, secondary to its dual agonist-antagonist effect on glucocorticoid receptors.

Wanke et al had similar results with AIDS patients. Patients were given megestrol 800 mg daily and at 5 weeks they reported a statistically significant weight increase of 2% (approximately 2.5 lbs). At week 12, patients reported a weight increase of 6% (or an average of 7.7 lbs).

Unfortunately, megestrol does not come without any adverse effects. Long-term use of megestrol had been associated with adrenal suppression, secondary to its dual agonist-antagonist effect on glucocorticoid receptors. Like other progesterones, megestrol increases the risk of thromboembolism (such as deep vein thrombosis (DVT) and pulmonary embolism (PE)). How often does megestrol cause DVTs in patients? In 2003, Kropsky et al conducted a retrospective study at a nursing home and revealed that there was a 6-fold increase of DVT risk in megestrol-users. The dose of megestrol was higher than the dose prescribed for the patient described below (40 mg BID).

The following case is about a nursing home resident who presents with a DVT. Was the DVT a result of megesterol?

LB is a 68-year old female who has generalized weakness, poor appetite and movement for the past 2 weeks. Upon review of the nursing notes, you note that the patient has skin tenting and a developing decubitus ulcer on the posterior of her right heel. Her past medical history includes Alzheimer’s disease, atrial fibrillation, COPD, diabetes mellitus, seizures, and schizophrenia. 

Her current vitals for the day are BP of 163/59, respiratory rate of 20, heart rate of 77, and she is afebrile. Her most recent labs (drawn two days ago) are sodium of 139 mEq/liter (slightly low), bicarb of 31 mEq/liter (slightly high), glucose of 93 mg/dl, BUN/Cr of 13/0.3, serum osmolality of 268 mOsm/kg (low), phenytoin level of 4.9 mcg/ml (low), albumin level is 2.6, INR 3.9, and a positive UA (with moderate leukocyte esterase and WBC). The rest of the chemistry panel is unremarkable. CBC is normal with WBC of 9.2 K/uL and H/H is 11.9/36.3. Her current weight is 51.8 kg (114 lbs) and height is 155 cm (5 feet).

Since the patient is complaining of right leg pain, presumably from the ulcer, the physician orders a Doppler ultrasound to ensure that a deep venous thromboembolism (DVT) didn’t form as well. Unfortunately, the results are positive for a DVT in the right common femoral and superficial femoral veins.

Her medication list includes Aricept 10 mg QHS, Tegretol 200 mg TID, warfarin 6 mg daily, digoxin 0.125 mg daily, phenytoin 100 mg QHS, Megace 40 mg BID, and Risperdal 0.5 mg QHS. To assess possible adverse drug reactions (ADRs), consider the following tips:

1. Monitor for medication compliance

It is well-known that non-compliance is common among patients. However, don’t be surprised to know that non-compliance also occurs with patients who reside in assisted living homes, nursing facilities, and hospitals. Don’t assume that a nursing staff guarantees that patients will take their medications. Review the nursing notes and documentation about compliance. Nursing documentation is very helpful. Sometimes, patients may refuse Miralax because they have diarrhea or cannot take their furosemide because they are too hypotensive. These notes can help the pharmacist make better recommendations. For example, you can recommend to “please stop Miralax secondary to diarrhea” or “please hold lisinopril and furosemide secondary to consistently low blood pressures (range: 90/55 to 110/65).”

In this case, the patient is compliant with all of her medications.

2. Review pertinent labs

The patient’s INR is supra-therapeutic at 3.9. The goal INR is 2.0 to 3.0 for atrial fibrillation. Warfarin has many drug-food interactions with vitamin K-containing foods. Since she lacks a normal appetite, the patient did not consume her normal amount of vegetables to counter some of the anticoagulant effects of warfarin and her warfarin dose of 6 mg daily was not adjusted. Her INR expectedly rose above goal. Her stable hemoglobin and hematocrit suggests that the patient is not actively bleeding. Therefore, it is acceptable to recommend to the physician to “hold warfarin until INR is below 3.0 and then resume dosing."

3. Assess for the likelihood of megestrol-associated DVT

Despite the elevated INR (from warfarin), the patient surprisingly develops a DVT. Risk factors for DVT include immobility, age, obesity, hormones, smoking, heart failure, inflammatory bowel disease, major surgery, injury to veins, pregnancy, cancer, history of DVT, and congenital coagulopathies such as Protein C and Protein S deficiency. Our patient has one risk factor: recent immobility of 2 weeks. Based on the above research on megestrol, it is possible that immobility and megestrol both led to the thromboembolism.  

4. Evaluate the need for megestrol

The patient’s family wants to continue the medication that “helps her eat more”. The physician is letting you decide. What do you think? It is true that megestrol can increase appetite, weight gain (non-fluid), and quality of life. These are important goals for the patient, family, and care takers. However, let us consider our patient. Currently, she weighs 51.8 kg. Based on her height, she has already reached her ideal body weight and has a normal BMI of 22. In this case, there is no added benefit from taking megestrol (even at low doses) and should be stopped. If megestrol is continued, the patient is exposed to a higher risk of future DVTs (including fatal PEs), adrenal suppression, and unnecessary weight gain.  

5. Report the possible adverse drug interaction (ADR) to MedWatch

In addition to your institution’s policy on adverse drug reaction reporting, you should also report serious or unusual ADRs to FDA’s MedWatch.

References

Yeh SS, Schuster MW. Megestrol acetate in cachexia and anorexia. Int J Nanomedicine. Dec 2006; 1(4): 411–416.

Wanke C, Gutierrez J, Kristensen A, et al. Safety and efficacy of two preparations of megestrol acetate in HIV-infected individuals with weight loss in Africa, India, and the United States. J Applied Res. 2007; 7(3):206-216.

Kropsky B, Shi Y, Cherniack EP. Incidence of deep-venous thrombosis in nursing home residents using megestrol acetate. J Am Med Dir Assoc. 2003 Sep-Oct; 4(5):255-6.