FORMULARY ADDITIONS

Toremifene, a chemical analogue of tamoxifen, is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or receptor unknown disease. Like tamoxifen, this agent works by blocking estrogen mediated growth stimulus of tumor cells. Toremifene is well-absorbed (bioavailability 100%) and has a mean elimination half-life of approximately five to six days. Steady state serum concentrations with oral administration are reached within 1 to 5 weeks. Toremifene undergoes significant metabolism via the cytochrome P450 3A4 isoenzyme system.

In multicenter comparative trials, toremifene (60 to 240 mg daily) and tamoxifen (20 or 40 mg daily) have had similar efficacy rates as first line endocrine treatment in postmenopausal women with advanced breast cancer. In addition, remission rates, time to disease progression and median overall survival time has been similar. Patients with tamoxifen resistant tumors have responded to second line therapy with high dose toremifene therapy (120 mg to 240 mg daily).

The adverse reaction profile of toremifene is very similar to that of tamoxifen, primarily related to the antiestrogenic hormonal actions. The most commonly reported reactions included hot flashes (35%), vaginal discharge (13%), nausea (14%) and sweating (20%). Drug interactions with toremifene are expected with inhibitors or inducers of the cytochrome P450 3A4 isoenzyme system. Increased daily doses may be required in those patients receiving enzyme inducers such as carbamazepine, phenytoin, and phenobarbital. Agents, which would inhibit metabolism, include erythromycin, clarithromycin, azole antifungals (i.e. itraconazole, ketoconazole) quinidine, verapamil, diltiazem and grapefruit juice. Concurrent administration of anticoagulants should be avoided and toremifene should also not be administered with medications that increase serum calcium levels, such as thiazide diuretics.

The recommended oral dose of toremifene is 60 mg once daily until disease progression is observed. As second line therapy doses of 120 mg to 240 mg daily have been of benefit in some patients, but this dosing schedule requires further evaluation.

Raloxifene (Evista)
60 mg Tablets

Raloxifene, a selective estrogen receptor modulator, has estrogen like effects on bone (increases bone mineral density) and on lipid metabolism (decreases in total and LDL cholesterol levels). Preliminary clinical data, however, suggests that raloxifene lacks the estrogen effects on the uterus and breast tissue. This drug is indicated for the prevention of osteoporosis in post-menopausal women. Raloxifene is absorbed rapidly after oral administration with approximately 60% of an oral dose absorbed. It undergoes extensive first pass metabolism to glucronide conjugates and it not metabolized by the cytochrome P450 pathways. Plasma elimination half-life approximates 27.7 hours after oral dosing.

This drug has been studied primarily in double blinded placebo controlled clinical trials which have demonstrated bone mineral density increases in the lumbar spine, total hip femoral neck, and total body. Reductions in cholesterol concentrations occurred with in the first three months of therapy and remained constant with continued therapy. No changes in HDL or triglycerides, or endometrial thickness were observed.

Like conjugated estrogen therapy, raloxifene is contraindicated for use in women who are or may become pregnant, and in women with an active or past history of venous thromboembolic events (e.g., DVT, pulmonary embolism and retina vein thrombosis). Unlike estrogen therapy, however, raloxifene is not contraindicated in patients with an estrogen dependent neoplasms (i.e. certain breast cancers). Raloxifene should not be used in premenopausal women or in patients with hepatic dysfunction. The concurrent use of raloxifene with estrogen therapy has not been studied and is not recommended.

When compared to continuous and cyclic hormone replacement therapy, raloxifene was associated with more hot flashes but fewer incidences of breast pain and vaginal bleeding. In clinical trials the most frequently cited adverse events included hot flashes (24.6%) and arthralgias (10.7%). An analysis of all placebo controlled data also revealed an increased risk of venous thromboembolic events, including DVT, pulmonary embolism and retinal vein thrombosis with the greatest risk occurring within the first four months of treatment. Thus, raloxifene should be discontinued at least 72 hours prior to and during prolonged immobilization (post-op recovery, prolonged bed rest) and should only be restarted once the patient is fully ambulatory.

Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be co-administered,. Raloxifene is greater than 95% protein bound and caution should be advised when administered with other highly protein bound drugs.

The recommended dosage for raloxifene is 60 mg daily administered at any time during the day.

Mibefradil, a chemically unique calcium channel blocker which binds to the verapamil type receptor of cardiac membranes, acts primarily as a vasodilator. It is indicated for the treatment of hypertension and chronic stable angina pectoris. Unlike verapamil and diltiazem, however, mibefradil does not have negative inotropic effects, except at high doses but does produce increases in coronary blood flow comparable to verapamil and less than diltiazem. Unlike other calcium channel blockers that act primarily on L-type calcium channels, mibefradil is selective for T type calcium channels. Although mibefradil is indicated for the treatment of hypertension and chronic stable angina pectoris, it is also being studied for its role in treating patients with ischemic chronic heart failure because it does not produce negative inotropic effects

Mibefradil plasma concentrations are dose proportional with a half-life of 17 to 25 hours. Elimination is by the biliary (75%) system into the urine (25%). In hepatic insufficiency, no clinically relevant changes were seen after single 100 mg doses, however, monitoring of blood pressure and heart rate is advised when administering mibefradil to patients with severe hepatic impairment.

Mibefradil is contraindicated in patients with sick sinus syndrome or second or third degree AV block without a pacemaker. In addition the coadministration of mibefradil with terfenadine, astemizole and cisapride are contraindicated. Because mibefradil inhibits the cytochrome P450 2D6 and 3A4 isoenzyme systems, drugs which effect these systems may interact. Mibefradil slows sinus and AV node conduction, sometimes resulting in abnormally low heart rates. Thus, patients with a pretreatment heart rate below 50 bpm should be followed closely. The most common adverse events associated with this drug include headache and leg edema.

For the treatment of hypertension or chronic stable angina, the manufacturer recommended dosing is 50 mg once daily. Titration to 100 mg once daily should be based on blood pressure response or therapeutic response, respectively. The full effect of a given dose level is generally seen after one to two weeks.

Return to PharmKey Home Page