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Pharmaceutical Approval Update September 2011

Marvin M. Goldenberg PhD, RPh, MS

Ticagrelor (Brilinta)

Manufacturer: Astra Zeneca, Wilmington, Del.

Indication: Ticagrelor is an oral P2Y12 platelet inhibitor that is designed to reduce the rate of thrombotic cardiovascular (CV) events in patients with acute coronary syndrome (ACS), which can include unstable angina, non–ST-elevation myocardial infarction (N-STEMI), or STEMI. Ticagrelor decreases the rate of a combined endpoint of CV death, MI, or stroke when compared with clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-aventis). In patients undergoing percutaneous coronary intervention (PCI), ticagrelor also reduces the rate of stent thrombosis.

Ticagrelor has been studied in combination with aspirin in patients with ACS. Maintenance doses of aspirin above 100 mg/day decreased the effectiveness of ticagrelor and should be avoided.

Like other antiplatelet drugs, ticagrelor can cause significant and sometimes fatal bleeding and should not be used in patients with active pathological bleeding.

Drug Class: Ticagrelor is the first drug in a new chemical class, the cyclopentyl-triazolo-pyrimidines. The molecular formula is C23H28F2N6O4S. The molecular weight is 522.57.

Uniqueness of Drug: This drug inhibits platelet aggregation, which is mediated by the P2Y12 adenosine diphosphate (ADP) receptor. Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent. Ticagrelor has a reversible P2Y12 platelet receptor inhibitory effect. In preclinical and early-phase clinical studies, the drug showed a rapid and consistent antiplatelet effect.

Boxed Warning: A bleeding risk has been shown with ticagrelor.

Warnings and Precautions:

Bleeding. Drugs that inhibit platelet function, including ticagrelor, increase the risk of bleeding. Compared with clopidogrel, ticagrelor increased the overall risk of major and minor bleeding to a somewhat greater extent. The increase was observed for bleeding not related to coronary artery bypass grafting (CABG), but it was not observed for CABG-related bleeding. Rates were not increased for fatal or life-threatening bleeding.

In general, risk factors for bleeding include older age, a history of bleeding disorders, PCI procedures, and the concomitant use of medications that increase the risk of bleeding, such as anticoagulants and fibrinolytics, high doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs (NSAIDs). When possible, ticagrelor should be discontinued 5 days before surgery. Bleeding should be suspected in all patients with hypertension who have recently undergone coronary angiography, PCI, CABG, or other procedures, even if there are no signs of bleeding. If possible, bleeding should be managed without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent CV events.

Aspirin maintenance dose. In the Study of Platelet Inhibition and Patient Outcomes (PLATO), the use of ticagrelor along with maintenance doses of aspirin above 100 mg decreased the effectiveness of ticagrelor. Therefore, after the initial loading dose of aspirin (usually 325 mg) is given, a maintenance dose of aspirin should be between 75 and 100 mg when used with ticagrelor.

Hepatic impairment. Ticagrelor has not been studied in patients with moderate hepatic impairment. Clinicians should consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.

Dyspnea. Dyspnea was reported in 14% of patients who were treated with ticagrelor and in 8% of patients taking clopidogrel. Dyspnea was usually mild to moderate and often resolved during continued treatment. If new, prolonged, or worsened dyspnea develops during ticagrelor treatment, clinicians should exclude underlying diseases that may require treatment. If dyspnea is found to be related to ticagrelor, no specific treatment is required. Ticagrelor may be continued without interruption.

In a substudy, 199 patients in PLATO underwent pulmonary function testing whether or not they had reported dyspnea. There was no significant difference between treatment groups for forced expiratory volume (FEV1). There was no indication of an adverse effect on pulmonary function assessed after 1 month or after at least 6 months of chronic treatment.

Discontinuation of therapy. Treatment should not be interrupted if ticagrelor must be temporarily discontinued, for example, to treat bleeding or during elective surgery. Therapy should be restarted as soon as possible. Discontinuation of ticagrelor increases the risk of MI, stent thrombosis, and death.

Strong inhibitors of cytochrome P450 3A. Ticagrelor is metabolized by cytochrome P450 (CYP) 3A4/5. It should not be used with strong CYP3A inhibitors, such as atazanavir (Reyataz, Bristol-Myers Squibb), clarithromycin (Biaxin, Abbott), indinavir (Crixivan, Merck), itraconazole (Sporanox, Janssen), ketoconazole (Nizoral, Janssen), nefazodone (Serzone, Bristol-Myers Squibb), nelfinavir (Viracept, Agouron), ritonavir (Norvir, Abbott), saquinavir (Invirase, Roche), telithromycin (Ketek, Sanofi-aventis), and voriconazole (Vfend, Pfizer).

Potent inducers of cytochrome P450 3A. Ticagrelor should be avoided with potent CYP3A inducers such as rifampin, dexamethasone, phenytoin (Dilantin, Pfizer), carbamaz-epine (Carbatrol, Shire), and phenobarbital.

Dosage and Administration: The initial oral loading dose of ticagrelor is 180 mg (two 90-mg tablets). Treatment is continued with 90 mg twice daily. After the initial loading dose of aspirin (usually 325 mg), the daily maintenance dose of aspirin is 75 to 100 mg.

Commentary: Ticagrelor has been approved to reduce rates of CV death and heart attack in patients with ACS, which comprises unstable angina or a heart attack that could result from reduced blood flow to the heart. Ticagrelor prevents the formation of new blood clots, thus maintaining blood flow in the body to help reduce the risk of another CV event.

Ticagrelor has been studied in combination with aspirin. A boxed warning states that aspirin doses above 100 mg/day decrease the effectiveness of the medication. In clinical trials, ticagrelor was more effective than clopidogrel in preventing heart attacks and death, but that advantage was seen with aspirin maintenance doses of 75 to 100 mg once daily.

Like other anticoagulants, ticagrelor increases the rate of bleeding and can cause significant, sometimes fatal bleeding. In clinical trials, the most common adverse reactions reported by patients taking ticagrelor were bleeding and difficulty breathing.

Ticagrelor is being dispensed with a patient medication guide each time a prescription is filled.

The wholesale cost is $7.24 per day, almost 20% more than the $6.08 wholesale price of its chief rival, clopidogrel. Ticagrelor also costs 25% more than the $5.78 wholesale cost of prasugrel (Effient, Eli Lilly/Daiichi Sankyo), another competitor.


Rivaroxaban (Xarelto)

Manufacturer: Janssen, Titusville, N.J.

Indication: Rivaroxaban oral tablets are indicated for the prevention of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients undergoing knee- or hip-replacement surgery.

Drug Class: Rivaroxaban (formerly, BAY 59-7939) is a selective factor Xa (FXa) inhibitor. Its chemical name is 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular weight is 435.89.

Uniqueness of Drug: Rivaroxaban is an orally bioavailable inhibitor of factor Xa. A cofactor (such as anti-thrombin III) is not required for activity. Activation of factor X to factor Xa via the intrinsic and extrinsic pathways plays a central role in the cascade of blood coagulation.

Boxed Warning: Epidural or spinal hematomas may occur in patients who have received anticoagulation therapy and who undergo neuraxial anesthesia or a spinal puncture, sometimes resulting in long-term or permanent paralysis. These risks should be considered when patients are scheduled for spinal surgery. Factors that can increase the risk of epidural or spinal hematomas include the use of indwelling epidural catheters, the concomitant use of other drugs that affect hemostasis, a history of traumatic or repeated epidural or spinal punctures, and a history of spinal deformity or spinal surgery.

Patients should be monitored frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. The benefits and risks of rivaroxaban should be considered before patients receive anticoagulation therapy and for patients who are to undergo neuraxial intervention or thromboprophylaxis.

Warnings and Precautions:

Spinal/epidural anesthesia or puncture. An epidural catheter should not be removed earlier than 18 hours after the last administration of rivaroxaban. The next dose should not be given earlier than 6 hours after removal of the catheter. If traumatic puncture occurs, rivaroxaban administration should be delayed for 24 hours.

Risk of bleeding. Rivaroxaban increases the risk of serious and fatal bleeding and should be used with caution in conditions that pose an increased risk of hemorrhage. The concomitant use of drugs that affect hemostasis increases the risk of bleeding. Bleeding can occur at any site during therapy with rivaroxaban. Any signs or symptoms of blood loss should be evaluated promptly.

Risk of pregnancy-related hemorrhage. Rivaroxaban must be used with caution in pregnant women. It should be dispensed only if the potential benefits justify the potential risks to the mother and fetus. This drug has not been studied in pregnant patients. The anticoagulant effect of rivaroxaban cannot be monitored with standard laboratory testing or readily reversed. Any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin or hematocrit, hypotension, or fetal distress) should be promptly evaluated.

Renal impairment. Rivaroxaban should be avoided in patients with severe renal impairment, specifically those with a creatinine clearance (CrCl) below 30 mL/minute, and the patient should be closely observed. Any signs or symptoms of blood loss in patients with moderate renal impairment (CrCl, 30–50 mL/minute) should be evaluated immediately. If renal failure occurs during rivaroxaban therapy, treatment should be discontinued.

Hepatic impairment. Rivaroxaban should not be administered to patients with moderate hepatic impairment (Child-Pugh B) because of the significant increase in exposure to the drug, to those with severe hepatic impairment (Child-Pugh C), and to those with any hepatic disease associated with coagulopathy.

Dosage and Administration: The recommended dosage of rivaroxaban is 10 mg orally once daily with or without food. The initial dose should be taken at least 6 to 10 hours after surgery after hemostasis has been established. For patients undergoing hip-replacement surgery, a treatment duration of 35 days is recommended. For patients undergoing knee-replacement surgery, a treatment duration of 12 days is recommended. If a rivaroxaban dose is not taken at the scheduled time, it should be taken as soon as possible on the same day and continued on the following day, once daily as recommended.

Commentary: The American College of Chest Physicians recommends the use of anticoagulants immediately after major orthopedic replacement surgery and the extended use of these drugs after discharge (at least 10 days for knee replacement and up to 35 days for hip replacement) to help reduce such risks. However, full compliance with these guidelines using previously available options has not been widely observed. DVT and PE are the leading causes of re-hospitalization following joint-replacement surgery.

Pivotal data from the phase 3 clinical development program showed significantly greater effects of rivaroxaban in a head-to-head comparison study with enoxaparin (Lovenox, Sanofi-aventis) and in a comparison of extended-duration rivaroxaban (for 5 weeks) with short-duration enoxaparin (for 2 weeks), followed by placebo. In these studies, rivaroxaban and enoxaparin demonstrated similar safety profiles, including low rates of major bleeding. Shorter hospital stays after hip- and knee-replacement surgery have made the prevention of venous blood clots an outpatient task, and rivaroxaban provides a safe oral treatment that can be easily used at home.

Unfortunately, rivaroxaban also showed a worse bleeding profile than low-molecular-weight heparin in a study of hospitalized, acutely ill patients. More studies are required to determine the implications of this finding.


Indacaterol Inhalation Powder (Arcapta Neohaler)

Manufacturer: Novartis, East Hanover, N.J.

Indication: Indacaterol inhalation powder is used for the long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis, emphysema, or both. The powder relaxes the muscles around the airways of the lungs to prevent wheezing and breathlessness. The powder is not intended to treat asthma or sudden, severe symptoms of COPD.

Long-acting beta2-adrenergic agonists (LABAs) increase the risk of asthma-related deaths and should not be used in patients with asthma unless a long-term control medication is being used.

Drug Class: Indacaterol maleate is a new molecular entity in the beta2-adrenergic agonist class. The molecular formula is C24H28N2O•C4H4O4. The molecular weight is 508.56.

Uniqueness of Drug: Indacaterol powder helps muscles around the airways of the lungs stay relaxed to prevent symptoms of COPD. When inhaled, this LABA acts locally in the lung as a bronchodilator. Although beta2-receptors are the predominant adrenergic receptors in the bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-adrenergic receptors in the heart that comprise 10% to 50% of the total.

Boxed Warning: LABAs increase the risk of asthma-related death and should not be used in patients with asthma unless these agents are used with a long-term asthma control medication.

Warnings and Precautions: Therapy with indacaterol should not be started in patients with acutely deteriorating COPD. This medication should not be used to relieve acute symptoms; if the patient has acute symptoms, they should be managed with concomitant short-acting beta2-agonists. If life-threatening paradoxical bronchospasm occurs, the use of indacaterol powder should be discontinued immediately.

Caution is recommended for patients with cardiovascular (CV) or convulsive disorders, thyrotoxicosis, or sensitivity to sympathomimetic drugs. The powder should also be used with caution with other adrenergic drugs, which may potentiate its effects, and with xanthine derivatives, steroids, diuretics, or non–potassium-sparing diuretics, which may potentiate hypokalemia or electrocardiographic (ECG) changes. Extreme caution is warranted when indacaterol is used with monoamine oxidase inhibitors, tricyclic antidepressants, and drugs that prolong the QTc interval, because these agents may potentiate CV effects. Beta blockers may reduce the efficacy of indacaterol and should be used only when necessary.

Indacaterol is a Pregnancy Category C drug. It should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. Because beta agonists may interfere with uterine contractility, indacaterol should be used during labor only if the benefits clearly outweigh the risks. Caution is warranted when the drug is administered during breast-feeding.

The safety and efficacy of indacaterol in pediatric patients have not been determined; therefore, the drug is not indicated for use in children. Studies have not been performed in patients with severe hepatic impairment or in those with renal impairment, but the urinary pathway contributes little to the total body elimination.

Dosage and Administration: Indacaterol is supplied as 75-mcg hard capsules that contain the powder. The product should be used with the Neohaler inhaler only, once daily every day. The capsules are not to be swallowed. The recommended dose should not be exceeded because excessive use of the drug, or use in conjunction with other LABA-containing medications, may cause clinically significant CV effects or even death.

No dosage adjustments are needed for geriatric patients or in patients with mild and moderate hepatic impairment.

Commentary: Indacaterol is the first once-daily therapy in the LABA class to be approved in the U.S. for the maintenance treatment of airflow obstruction in patients with COPD. With millions of Americans affected by COPD, the approval is important news for patients with this debilitating disease.

A dose of 75 mcg was studied in 641 COPD patients in two key phase 3 trials lasting 12 weeks. Results at week 12 showed that the product significantly improved lung function at 24 hours compared with placebo. Lung function improvements were seen 5 minutes after the first dose and were consistently maintained over 12 weeks. Indacaterol also significantly reduced the need for a daily rescue medication.

Indacaterol improved health-related quality of life better than placebo, as assessed by the St. George’s Respiratory Questionnaire, a widely used instrument that measures symptoms, activities, and the impact of COPD on daily life, as reported by patients.

Common adverse reactions in 449 patients taking 75 mcg of the powder (i.e., reported in more than 2% of patients) were cough, nasopharyngitis, headache, nausea, and oropharyngeal pain. A patient medication guide is included with the product.