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P T. 2012;37(2): 80, 84-85

Pharmaceutical Approval Update February 2012

Marvin M. Goldenberg PhD, RPh, MS

Antihemophilic Factor [Recombinant] Plasma/Albumin Free Method (Advate)

Manufacturer: Baxter Healthcare, Westlake Village, Calif.

Indication: Advate, a biologic product, is used as routine prophylaxis to control and reduce the frequency of bleeding episodes in adults and children with hemophilia A. It is not indicated for patients with von Willebrand’s disease.

Biological Class: As a purified glycoprotein consisting of 2,332 amino acids, Advate is synthesized by a genetically engineered Chinese hamster ovary (CHO) cell line. In culture, the CHO cell line expresses recombinant antihemophilic factor (rAHF) into the cell culture medium. rAHF is purified from the culture medium by the use of a series of chromatography columns.

The purification process includes a step that involves immunoaffinity chromatography, during which a monoclonal antibody directed against Factor VIII is used to selectively isolate rAHF from the medium. The cell culture and purification processes used in the manufacture of antihemophilic factor (AHF) do not use any additives of human or animal origin. A dedicated, virus-inactivation, solvent-detergent treatment step is included in the production process. rAHF has the same biological effects on clotting as human AHF. Structurally, recombinant protein combines both heterogeneous heavy and light chains similar to those found in human AHF.

Uniqueness of Biologic: AHF temporarily replaces the missing clotting Factor VIII, which is required for effective hemostasis. Advate is the only rAHF approved in the U.S. for perioperative control and prevention of bleeding in patients with hemophilia A.

Warnings and Precautions: Clinical responses may vary. If bleeding is not controlled with the recommended dose, the plasma concentration of Factor VIII should be determined and a sufficient dose of Advate should be administered to achieve a satisfactory clinical response. If the patient’s plasma Factor VIII level is not increased as expected, or if bleeding is not controlled after the expected dose, the presence of any inhibitors, such as neutralizing antibodies, should be suspected and appropriate testing should be performed.

Anaphylaxis and hypersensitivity reactions. Allergic-type reactions, including anaphylaxis, have been reported with AHF. Symptoms have included dizziness, paresthesias, rash, flushing, face swelling, urticaria, dyspnea, and pruritus. Advate contains trace amounts of mouse immunoglobulin G (a maximum of 0.1 ng/IU in AHF) and hamster proteins (a maximum of 1.5 ng/IU in AHF). Patients receiving this drug may experience hypersensitivity to non-human mammalian proteins. AHF should be discontinued if hypersensitivity symptoms occur, and emergency treatment should be administered.

Neutralizing antibodies. Patients who are treated with AHF products should be carefully observed and tested for the development of Factor VIII inhibitors. Inhibitors have been reported after the administration of AHF, predominantly in previously untreated patients and in previously minimally treated patients. If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures Factor VIII inhibitor concentration should be performed.

Laboratory tests: When indicated, plasma Factor VIII activity concentrations should be monitored by the one-stage clotting assay to confirm that adequate Factor VIII levels have been achieved and maintained. The development of Factor VIII inhibitors should also be monitored. The Bethesda assay should be performed to determine whether Factor VIII inhibitor is present, and Bethesda Units (BU) should be used to determine the inhibitor titer.

If the inhibitor titer is less than 10 BU/mL, adding more AHF concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response. If inhibitor titer exceeds 10 BU/mL, adequate hemostasis might not be achieved. As a result of an anamnestic response to Factor VIII, the inhibitor titer may rise following an Advate infusion. For these patients, alternative therapeutic approaches and agents are required to treat or prevent bleeding.

Dosage and Administration: Advate is available as a lyophilized powder in single-use glass vials that contain 250, 500, 1,000, 1,500, 2,000, or 3,000 International Units (IU). The product is intended only for intravenous (IV) use after reconstitution. Each vial is labeled with rAHF activity, which is expressed in IU per vial. A Factor VIII concentrate standard is used and is referenced to a World Health Organization International Standard for Factor VIII concentrates.

The specific activity of Advate is 4,000 to 10,000 IU/mg of protein. The recombinant Factor VIII potency, in IU, is stated on the label of each vial. The dosage and duration depend on the severity of Factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Therapy should be initiated under the supervision of a physician experienced in the treatment of hemophilia A.

Commentary: The FDA’s approval of Advate was based on a company-sponsored phase 4 prophylaxis study. The study demonstrated a statistically significant reduction in the median annual bleeding rate. Patients experienced 44 bleeding episodes (per patient per year) during on-demand treatment, compared with one bleeding episode (per patient per year) with either prophylactic regimen, for a 98% reduction in the annual bleeding rate. Nearly half (42%) of patients experienced no bleeding episodes during 1 year of prophylactic treatment. Evaluable patients adhered to the prescribed regimen at a rate of 90% or more. Although the trial was not powered to show equivalence in bleeding rates between the two prophylaxis arms, the difference in frequency of bleeding between the two regimens was not statistically significant.

Data from the study are important in aiding physicians who care for hemophilia patients.


Azilsartan Medoxomil (Edarbi) and Azilsartan Medoxomil/Chlorthalidone (Edarbyclor)

Manufacturer: Takeda Pharmaceuticals North America, Deerfield, Ill.

Indication: Both Edarbi and Edarbyclor are used in the treatment of hypertension. Edarbyclor (azilsartan medoxomil and chlorthalidone) is a fixed-dose combination therapy for the treatment of hypertension that combines azilsartan medoxomil (Edarbi) and chlorthalidone in a single tablet. Chlorthalidone reduces the amount of water in the body by increasing the flow of urine, which helps to lower blood pressure (BP). Edarbyclor may be used as an initial therapy if multiple drugs are likely to be needed to achieve BP control. Both products may be used with other antihypertensive agents.

Drug Class: Edarbi is an angiotensin II receptor blocker (ARB), and Edarbyclor comprises an ARB and a thiazide-like diuretic.

Uniqueness of Drug: Edarbyclor is the first fixed-dose combination medication in the U.S. that combines an ARB with the diuretic chlorthalidone. Lowering BP reduces the risk of cardiovascular events, primarily strokes and myocardial infarction (MI). No controlled trials have demonstrated risk reduction with Edarbi or Edarbyclor, but trials with chlorthalidone, as well as at least one drug that is pharmacologically similar to azilsartan medoxomil, have demonstrated this benefit.

Boxed Warning: When pregnancy is detected, Edarbi or Edarbyclor should be discontinued as soon as possible. Drugs that act directly on the renin–angiotensin system (RAS) can cause injury and death to the developing fetus.

Warnings and Precautions: Drugs that act directly on the RAS during the second and third trimesters of pregnancy have been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; in this setting, oligohydramnios has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were a result of exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure when limited to the first trimester. Mothers whose embryo or fetus is exposed to an ARB only during the first trimester should be informed of the potential hazard; nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Edarbi as soon as possible.

Rarely (probably less often than once in every 1,000 pregnancies), there is no alternative agent to a drug that affects the RAS. In these rare cases, the mother should be apprised of the potential hazards to the fetus. Serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Edarbi should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing, a non-stress test, or biophysical profiling may be appropriate, depending upon the week of gestation. However, patients and physicians should be aware that oligohydramnios might not appear until after the fetus has sustained irreversible injury.

Infants with a history of in utero exposure to an ARB should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of BP and renal perfusion. Exchange transfusion or dialysis may be required to reverse hypotension or substitute for impaired renal function.

Hypotension in volume-depleted or salt-depleted patients. Edarbyclor is contraindicated in patients with anuria. In patients with an activated RAS, such as those being treated with high doses of diuretics, symptomatic hypotension may occur after initial treatment with Edarbi. Volume or salt depletion should be corrected before Edarbi is given, or the initial dose should be 40 mg. If hypotension does occur, the patient should be placed in the supine position and, if necessary, should receive an IV infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty after BP has stabilized.

Impaired renal function: As a consequence of RAS inhibition, changes in renal function may be anticipated in some individuals receiving Edarbi. In patients whose renal function may depend on the activity of the RAS (e.g., those with severe congestive heart failure, renal artery stenosis, or volume depletion), angiotensin-converting enzyme (ACE) inhibitors and ARBs have been associated with oliguria or progressive azotemia but rarely with acute renal failure or death. Similar results may be anticipated with Edarbi.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen levels have been reported. Data are not available on the long-term use of Edarbi in these patients, but similar results may be expected.

Dosage and Administration: The recommended dose of Edarbi in adults is 80 mg taken orally once daily. A starting dose of 40 mg can be considered for patients receiving high doses of diuretics. The recommended starting dose of Edarbyclor is 40 mg/12.5 mg of azilsartan/chlorthalidone; the maximum dose is 40 mg/25 mg, respectively.

If BP is not controlled with Edarbi alone, a reduction in BP might be able to be achieved with Edarbi plus other anti-hypertensive agents. Edarbi may be taken with or without food.

Edarbi should not be repackaged. It should be dispensed and stored in its original container, and it should be protected from light and moisture.

No initial dose adjustments are recommended for elderly patients or for those with mild-to-severe renal impairment, end-stage renal disease, or mild-to-moderate hepatic dysfunction. Edarbi has not been studied in patients with severe hepatic impairment.

Commentary: Hypertension affects about 75 million Americans (one in three adults), or more than half of people 60 years of age and older. Azilsartan medoxomil (Edarbi) and azilsartan medoxomil/chlorthalidone (Edarbyclor) are used to reduce BP. Edarbyclor combines Edarbi (an ARB that helps blood vessels to stay relaxed and open) with a diuretic (chlorthalidone, which increases the flow of urine from the body, thereby lowering BP).

Elevated systolic or diastolic BP increases cardiovascular risk, and the absolute risk increase per millimeter of mercury (mm Hg) is greater at higher BPs. Therefore, even modest reductions in severe hypertension can provide substantial benefits. Both Edarbi and Edarbyclor should benefit all patients at risk for hypertension. The absolute benefit is greater in patients who are at higher risk, whether or not they have hypertension, such as those with diabetes or hyperlipidemia. This patient population would be expected to benefit from more aggressive treatment to a lower BP goal.

The FDA approved Edarbi in February 2011 and Edarbyclor in December 2011.


Oxybutynin Gel 3% (Anturol)

Manufacturer: Watson Pharmaceuticals, Inc., Parsippany, N.J./Antares Pharma Inc., Ewing, N.J.

Indication: Oxybutynin topical gel 3% was approved for the treatment of overactive bladder (OAB) accompanied by urge urinary incontinence, urgency, and frequency.

Drug Class: The main active metabolite of oxybutynin is desethyl-oxybutynin (DEO), which has an anticholinergic effect similar to that of oxybutynin, but it is primarily responsible for the anticholinergic side effects (dry mouth, dry eyes, constipation, or nausea). The translucent topical hydro-alcoholic gel contains oxybutynin, an antispasmodic, anti-muscarinic agent.

Uniqueness of Drug: Transdermal delivery of oxybutynin avoids first-pass metabolism in the liver, thereby reducing the formation of the DEO metabolite and associated adverse effects.

Warnings and Precautions:

Urinary retention. The gel should be used with caution in patients with significant bladder outflow obstruction because of the risk of urinary retention.

Digestive system disorders. Caution is indicated for patients with gastrointestinal (GI) obstructive disorders because of the risk of gastric retention. Like other anticholinergic drugs, the gel may decrease GI motility and should be used with care in (1) patients with ulcerative colitis or intestinal atony and (2) those with gastroesophageal reflux disease (GERD) and those who are currently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis.

Skin transference. Transfer of oxybutynin can occur if the application site of the patient comes into vigorous bare contact with the skin of another person. To minimize the potential of gel transference to another person, patients should cover the application site with clothing after the gel has dried if direct skin-to skin contact at the application site is anticipated. Patients should wash their hands immediately after they apply the gel.

Flammability. As an alcohol-based gel, Anturol is flammable. Patients should avoid open fires or smoking until the gel has dried.

Myasthenia gravis. Oxybutynin gel 3% should be applied with caution in patients with myasthenia gravis, which is characterized by decreased cholinergic activity at the neuromuscular junction.

Angioedema. Angioedema has occurred with the first or subsequent doses of oral oxybutynin, resulting in the need for patients to be hospitalized or to need emergency medical treatment. If angioedema occurs, the oxybutynin-containing product should be discontinued and appropriate therapy should be promptly provided.

Controlled narrow-angle glaucoma. The gel should be administered with caution in patients who are being treated for narrow-angle glaucoma.

Dosage and Administration: Anturol Gel 3%, 84 mg (approximately 3 mL), is applied once daily to dry, intact skin on the thigh, abdomen, upper arm, or shoulder. A consistent dose of oxybutynin is delivered through the skin over a 24-hour period. This formulation provides efficacy and maintains tolerability.

Delivered via a metered-dose pump, oxybutynin gel is systemically absorbed through the skin in a controlled manner. The pump must be primed before it is used for the first time. The patient should hold the pump upright and fully press the pump down four times. Any gel that was released during priming should not be used.

Anturol Gel 3% is intended for dermatological use only. It should not be applied on the breasts or genital areas, recently shaved skin, open sores, scars, tattoos, or skin with a rash. If skin-to-skin contact between another person and the application site is expected, the patient should cover the application site with clothing after the gel has dried. After applying the gel, patients should wash their hands with soap and water right away. The product may be used with sunscreen. If the gel gets into the patient’s eyes, the eyes should be rinsed well immediately with clean, warm water.

Commentary: Overactive bladder (OAB) is characterized by a sudden, uncomfortable need to urinate, with or without urge incontinence, and usually includes an increased incidence of urination and nocturia. OAB affects as many as 33 million adults in the U.S.—more than diabetes or asthma.

OAB is not only inconvenient; it is disabling and is associated with a marked decrease in health-related quality of life as well as in higher rates of depression. The disease affects both men and women, although women experience more severe symptoms earlier in life.

In several large studies, OAB affected approximately 16% of adults. The incidence of OAB increases with age. Approximately 100 million people worldwide and up to 50% of elderly residents in nursing homes experience symptoms of OAB.

Pharmacotherapy relies on the use of anticholinergic drugs, which block the parasympathetic acetylcholine pathway and thus abolish or reduce the intensity of detrusor muscle contraction. Anturol Gel 3% was approved on December 7, 2011. Oxybutynin in tablet form (Ditropan, Ortho-McNeil) was first approved in 1975 and still accounts for about 35% of prescriptions currently written to treat OAB.