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P T. 2013;38(12): 747-748, 754

Pharmaceutical Approval Update December 2013

Marvin M. Goldenberg PhD, RPh, MS

Conjugated Estrogens/Bazedoxifene (Duavee) Tablets

Manufacturer: Wyeth/Pfizer/Ligand, Philadelphia, Pa.

Indication: Duavee is indicated for women with a uterus who experience moderate-to-severe vasomotor symptoms (hot flashes) associated with menopause. The medication is also used to prevent osteoporosis after menopause.

Drug Class: Conjugated estrogens comprise a mixture of sodium estrone sulfate, sodium equilin sulfate, and other components, including sodium sulfate conjugates, 17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin. Bazedoxifene is a third-generation selective estrogen receptor modulator (SERM).

Uniqueness of Drug: This is the first medication to combine estrogen with an estrogen agonist/antagonist (bazedoxifene). The bazedoxifene component reduces the risk of endometrial hyperplasia that can occur with the estrogen component of the drug.

Boxed Warning: Patients should not take additional estrogens, progestins, or estrogen agonists/antagonists while they are taking Duavee. Estrogen may increase the risk of uterine cancer, dementia, and blood clots.

Patients should report any unusual vaginal bleeding if it occurs. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus. Estrogens should not be used to prevent heart disease, heart attacks, strokes, or dementia.

Warnings and Precautions: Duavee should not be used in women who are allergic to any of its ingredients; who have unusual vaginal bleeding; or who have or had uterine or breast cancer, liver abnormalities, or clotting or bleeding disorders. Duavee is not indicated for women who are pregnant, who may become pregnant, or who are breastfeeding.

The use of estrogen alone has been reported to result in an increase in abnormal mammograms requiring further evaluation. The effect of Duavee on the risk of breast and ovarian cancer is unknown.

Estrogens increase the risk of gallbladder disease. Duavee should be discontinued if loss of vision, severe hypertriglyceridemia, or cholestatic jaundice occurs. The risks of cardiovascular disorders and loss of vision, may be increased with Duavee. Women taking thyroid hormone should be closely monitored.

Dosage and Administration: Duavee (bazedoxifene/conjugated estrogens) is available as a 20-mg/0.45-mg tablet.

Commentary: Survey data indicate that approximately 50% of postmenopausal women experience moderate-to-severe vasomotor symptoms (hot flashes). When the estrogen levels begin dropping, some women experience feelings of warmth in the face, neck, and chest or sudden intense episodes of heat and sweating.

Like other products containing estrogen, Duavee should be used for the shortest duration possible. For the prevention of osteoporosis, the use of Duavee should be limited to patients after alternatives that do not contain estrogen have been considered.

Sources: www.fda.gov; www.pfizerpro.com/hcp/duavee

Riociguat (Adempas) Tablets

Manufacturer: Bayer HealthCare, Wayne, N.J.

Indication: Riociguat is used to treat persistent or recurrent chronic thromboembolic pulmonary hypertension (PH) after surgery or inoperable PH in adults to improve exercise capacity. It is also used in adults with pulmonary arterial hypertension (PAH) to improve exercise capacity and to delay clinical worsening.

Drug Class: Riociguat is a soluble guanylate stimulator that helps the arteries to relax. The drug’s chemical name is methyl (4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin3-yl)pyrimidin-5-yl)(methyl)carbamate. The molecular formula is C20H19FN8O2, and the molecular weight is 422.42 g/mol.

Uniqueness of Drug: Riociguat is the only treatment approved in the U.S. for use in two types of PH. It stimulates soluble guanylate cyclase (sGC), an enzyme in the cardio-pulmonary system and the receptor for nitric oxide (NO). NO binds to sGC and catalyzes synthesis of cyclic guanosine monophosphate (cGMP), which in turn activates protein kinase G regulation of cytosolic calcium ion concentration. This cascade changes actin–myosin contractility, resulting in vasodilation.

In healthy individuals, NO acts as a signaling molecule on vascular smooth muscle cells to induce vasodilation. NO binds to sGC and mediates the synthesis of the secondary messenger cGMP. sGC forms heterodimers consisting of a larger alpha-subunit and a smaller heme-binding beta-subunit. The synthesized cGMP acts as a secondary messenger and activates cGMP-dependent protein kinase (protein kinase G) to regulate cytosolic calcium ion concentration.

In patients with PAH, levels of endothelial NO synthase (the enzyme responsible for the production of NO) are reduced. This results in overall lower levels of endothelial cell–derived NO and reduced vasodilation of smooth muscle cells. NO also reduces pulmonary smooth muscle cell growth and antagonizes platelet inhibition, factors that play a key role in the pathogenesis of PAH.

In contrast to NO-independent and heme-independent sGC activators like cinaciguat (Bayer), riociguat stimulates sGC directly. It also stimulates sGC activity independently of NO and acts in synergy with NO to produce antiaggregatory, anti-proliferative, and vasodilatory effects.

Boxed Warning: Riociguat is not intended for use in pregnant women because of the risk of harm to the fetus. For females of reproductive age, pregnancy tests should be negative before treatment starts, monthly during treatment, and 1 month after stopping treatment.

This medication is available only through the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.

Warnings and Precautions:

Embryofetal toxicity. Riociguat may cause fetal harm when it is taken during pregnancy; therefore, it is contra-indicated in pregnant women. In females of reproductive age, pregnancy should be ruled out before therapy begins. An effective contraception method should be used, and pregnancy tests should be performed monthly.

REMS Program. Patients may receive riociguat only through the Adempas REMS restricted distribution program. Prescribers must be certified with the program by enrolling and completing training. All female patients must enroll in the program before beginning treatment. Male patients do not need to enroll. Pharmacies must be certified and may dispense the drug only to patients who are authorized to receive it.

Hypotension. Blood pressure may be reduced with treatment. Clinicians should consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensive drugs or strong cytochrome P450 and P-glycoprotein/breast cancer-resistant protein inhibitors. A dose reduction should be considered if hypotension symptoms develop.

Bleeding. In placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients receiving riociguat compared with none of the patients receiving placebo. Serious hemoptysis occurred in five patients (1%) who were taking riociguat and in none of the placebo patients; one patient died. Serious hemorrhagic events included vaginal, catheter-site, and intra-abdominal hemorrhages; subdural hematoma; and hematemesis.

Pulmonary veno-occlusive disease. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of riociguat is not recommended for these patients. If signs of pulmonary edema occur, the possibility of associated PVOD should be considered. If a diagnosis of PVOD is confirmed, riociguat should be discontinued.

Dosage and Administration: For patients with PH, the initial dose is 1 mg three times daily. If patients do not tolerate a hypotensive effect, a dose of 0.5 mg three times daily can be considered. If systolic blood pressure exceeds 95 mm Hg and no symptoms of hypotension occur, the dose can be titrated upward by 0.5 mg three times daily. Dose increases to the highest tolerated dose should occur no sooner than 2 weeks apart and should not exceed 2.5 mg three times daily. If symptoms of hypotension occur, the dose should be decreased by 0.5 mg three times daily.

Commentary: PAH is associated with endothelial dysfunction, impaired synthesis of NO, and insufficient stimulation of the NO–sGC–cGMP pathway. Riociguat sensitizes sGC to endogenous NO by stabilizing NO-sGC binding; it also directly stimulates sGC via a different binding site independently of NO.

Riociguat is the only medication approved in the U.S. for the treatment of both PH and PAH. It is also the only approved oral therapy for PAH that has shown efficacy as monotherapy or in combination with endothelin receptor antagonists or prostanoids. The medication promotes increased blood flow and decreases blood pressure.

Sources: www.fda.gov; http://pharma.bayer.com; www.adempas-us.com/index/php

Macitentan (Opsumit) Tablets

Manufacturer: Actelion, San Francisco, Calif.

Indication: Macitentan is used to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive and debilitating disease that can lead to death or the need for lung transplantation.

Drug Class: Macitentan is an endothelin (ET) receptor antagonist that relaxes the pulmonary arteries and decreases blood pressure in the arteries that connect the heart to the lungs. The drug’s chemical formula is N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N′-pro-pylaminosulfonamide. The molecular formula is C19H20Br2N6O4S, and the molecular weight is 588.27.

Uniqueness of Drug: Macitentan inhibits ET receptors and optimizes physicochemical properties to achieve high affinity for a lipophilic milieu. In vivo, macitentan is metabolized into a major pharmacologically active metabolite, ACT-132577. Macitentan and its metabolite antagonize the specific binding of ET-1 on membranes of cells overexpressing ETA and ETB receptors and blunted ET-1–induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ETA receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ETB receptors). In rats with pulmonary hypertension (PH), macitentan prevented an increase in pulmonary pressure and right ventricle hypertrophy and improved survival.

Boxed Warning:

Serious birth defects. Macitentan can cause serious birth defects if it is taken during pregnancy. Female patients must not be pregnant when they start therapy. They must also have a negative pregnancy test each month during treatment and at 1 month after stopping treatment. These recommendations apply to female patients who have entered puberty, even if they have not started their menstrual period; who have a uterus; and who have not gone through menopause. Females of childbearing age must use two acceptable forms of birth control during treatment and for 1 month after stopping therapy to address residual medication in the tissues. If the patient has had a tubal sterilization, has a progesterone implant, or has an intrauterine device in place, no other form of birth control is needed.

Patients should not have unprotected sexual relations. They should consult their health care professional if they miss a menstrual period or think that they might be pregnant. Parents and caregivers should consult with a physician if signs of puberty are developing in the child.

REMS Program. Female patients may receive macitentan only through the restricted Opsumit Risk Evaluation and Mitigation Strategy (REMS) Program. Male patients may receive macitentan without taking part in the Opsumit REMS Program.

Warnings and Precautions:

Embryofetal toxicity. Macitentan may cause fetal harm if taken during pregnancy. It is contraindicated in females who are pregnant. In females of childbearing age, pregnancy must be ruled out before treatment starts. An acceptable contraceptive method must be approved, and monthly pregnancy tests must be conducted.

REMS program. Macitentan is available for females through the Opsumit REMS restricted distribution program because of the risk of embryofetal toxicity.

Hepatotoxicity. Endothelin receptor antagonists have caused hepatotoxicity, liver failure, and elevated aminotransferase levels. Patients should be advised to report symptoms suggesting hepatic injury (nausea, vomiting, right upper-quadrant pain, fatigue, anorexia, jaundice, dark-colored urine, fever, or itching). If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin more than two times the upper limit of normal (ULN), macitentan should be discontinued.

Decreased hemoglobin production. Transfusions are seldom needed if hemoglobin levels are decreased. Macitentan is not recommended in patients with severe anemia. Hemoglobin production should be assessed before and during treatment as indicated.

Pulmonary edema or pulmonary veno-occlusive disease. If signs of pulmonary edema occur, the possibility of associated pulmonary veno-occlusive disease (PVOD) should be considered. If a diagnosis of PVOD is confirmed, therapy should be stopped.

Decreased sperm counts. Endothelin receptor blockers have had negative effects on spermatogenesis. Men should be counseled about the potential effects of macitentan on fertility.

Commentary: Macitentan (Opsumit) was approved as a therapy for adults with PAH, which is characterized by high blood pressure in the pulmonary arteries. PAH causes the right side of the heart to work harder than normal, which can lead to limitations on exercise ability and shortness of breath. Endothelin receptor blockers relax the pulmonary arteries, decreasing blood pressure in the lungs.

In a study lasting approximately 2 years, macitentan was effective in delaying disease progression and in preventing a decline in exercise ability and in worsening symptoms. It also reduced the need for additional medication for PAH.

Sources: www.fda.gov; www1.actelion.com; www.opsumit.com; www.opsumitrems.com