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Pharmaceutical Approval Update August 2013

Marvin M. Goldenberg PhD, RPh, MS

Canagliflozin (Invokana) Tablets

Manufacturer: Janssen Pharmaceuticals, Inc., Titusville, N.J.

Indication: The FDA approved canagliflozin in March 2013 as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus. This medication is not recommended for individuals with type-1 diabetes or for those with diabetic ketoacidosis.

Drug Class: Canagliflozin is the first approved diabetes treatment in a new class of drugs known as sodium–glucose co-transporter 2 (SGLT-2) inhibitors.

Uniqueness of Drug: Canagliflozin blocks the reabsorption of glucose by the kidney; it lowers blood glucose levels by increasing the renal loss of glucose into the urine. Although this mechanism is not dependent on the availability of insulin, canagliflozin has not been approved for type-1 diabetes. Because SGLT-2 inhibitors require glomerular filtration to generate tubular urine from which glucose reabsorption can be blocked, patients with a low glomerular filtration rate (GFR) experience little benefit with canagliflozin.

Warnings and Precautions:

Hypotension. Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur, particularly in patients with impaired renal function, defined as an estimated GFR (eGFR) below 60 mL/minute/1.73 m2, in elderly patients, in patients with low systolic blood pressure, and in patients taking diuretics or medications that interfere with the renin–angiotensin–aldosterone system (RAAS). Examples of such medications include angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs). Before patients with these characteristics begin therapy, their volume status should be assessed and corrected. Signs and symptoms should be monitored after therapy is initiated.

Impaired renal function. Canagliflozin may cause elevated serum creatinine levels and decreases in eGFR. Patients with hypovolemia may be more susceptible to these changes. Abnormalities in renal function can occur with the start of canagliflozin therapy. More frequent monitoring of renal function is recommended in patients with an eGFR below 60 mL/ minute/1.73 m2.

Hyperkalemia. Canagliflozin can lead to elevated potassium levels. Hyperkalemia is more likely to develop in patients with moderate renal impairment who are taking drugs that interfere with potassium excretion. Examples include potassium-sparing diuretics and drugs that interfere with the RAAS. Serum potassium levels should be monitored periodically in patients with impaired renal function and in patients predisposed to hyperkalemia resulting from medications or other medical conditions.

Hypoglycemia. Canagliflozin can increase the risk of hypoglycemia when it is combined with insulin or insulin secretagogues, which are known to cause hypoglycemia. Therefore, a lower dose of insulin or the insulin secretagogue may be required to minimize the risk of hypoglycemia in patients taking canagliflozin.

Genital fungal infections. Canagliflozin increases the risk of genital mycotic infections, especially in uncircumcised males and patients with a history of these infections. Patients should be monitored and treated appropriately.

Hypersensitivity reactions. Generalized urticaria and serious hypersensitivity reactions have been reported with canagliflozin; these reactions generally occurred within hours to days after therapy began. If hypersensitivity reactions occur, the medication should be discontinued. Patients should receive the standard of care and should be monitored until signs and symptoms resolve.

Elevated LDL-cholesterol. Dose-related increases in low-density lipoprotein-cholesterol (LDL-C) levels have occurred with canagliflozin. LDL-C levels should be monitored, and patients should receive the standard of care.

Macrovascular outcomes. No clinical studies have established evidence of a reduced macrovascular risk with canagliflozin or any other antidiabetic drug.

Contraindications: Patients with a history of a serious hypersensitivity reaction to canagliflozin, patients with severe renal impairment (eGFR below 30 mL/minute/1.73 m2), those with end-stage renal disease, and dialysis patients should not take canagliflozin.

Dosage and Administration: The recommended starting dose of canagliflozin is 100 mg once daily, taken before the first meal of the day. The dose can be increased to 300 mg once daily if the 100-mg once-daily dose is tolerated, if the patient’s eGFR is 60 mL/minute/1.73 m2 or greater, and if additional glycemic control is required.

For patients with mild renal impairment (eGFR of 60 mL/minute/1.73 m2 or greater), no dosage adjustments are needed.

For patients with moderate renal impairment (eGFR between 45 and 60 mL/minute/1.73 m2), the dose should be limited to 100 mg once daily.

For patients with an eGFR of less than 45 mL/minute/1.73 m2, canagliflozin should not be initiated.

Assessment of renal function is recommended before canagliflozin therapy begins and periodically during treatment. Canagliflozin should be discontinued if the eGFR continues to be less than 45 mL/minute/1.73 m2.

Use with UDP-glucuronosyl transferase (UGT). If an inducer of UGT (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is administered with canagliflozin, the dose of canagliflozin can be increased to 300 mg once daily in patients who tolerate 100 mg once daily, whose eGFR is 60 mL/minute/1.73 m2 or greater, and who require additional glycemic control. Another antihyperglycemic agent should be considered in patients whose eGFR is between 45 and 60 mL/minute/1.73 m2 and who are also receiving a UGT inducer.

Commentary: Type-2 diabetes is the most common form of the disease, accounting for more than 90% of diabetes cases diagnosed in the U.S. Over time, high glucose levels can increase the risk for heart disease, blindness, and nerve and kidney damage. The FDA is requiring postmarketing studies for canagliflozin to monitor for cardiovascular problems, malignancies, pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, adverse pregnancy outcomes, and bone safety. The agency also plans to conduct two pediatric studies.


Denosumab (Xgeva) Injection

Manufacturer: Amgen, Thousand Oaks, Calif.

Indication: Denosumab as Xgeva has been granted an expanded indication for the treatment of giant-cell tumor of bone, a rare and usually noncancerous tumor that is unresectable or that is likely to result in severe morbidity if surgical resection is performed. The drug is intended for adults and skeletally mature adolescents. Xgeva was originally indicated to prevent skeletal-related events in patients with bone metastases from solid tumors.

Biologic Class: Denosumab is a human immunoglobulin G2 (IgG2) monoclonal antibody that binds to the human RANK ligand (RANKL), a protein essential for maintenance of healthy bone. RANKL is also present in giant-cell tumor of bone. The drug’s approximate molecular weight is 147 kilodaltons.

Uniqueness of Biologic Product: Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts, their precursors, and osteoclast-like giant cells. RANKL is a protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Giant-cell tumors of bone consist of stromal cells expressing RANKL and osteoclast-like giant cells expressing RANK receptor. Signaling through the RANK receptor contributes to osteolysis and tumor growth. The drug is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

Warnings and Precautions:

Hypocalcemia. Denosumab can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Symptoms may include tetany and cardiac arrhythmias. Pre-existing hypocalcemia should be corrected before denosumab is initiated. Calcium levels should be monitored, and calcium, magnesium, and vitamin D should be administered as necessary. Monitoring should be performed more frequently when denosumab is given with other drugs that might also lower calcium levels. Patients should be advised to contact a health care professional if they experience symptoms of hypocalcemia.

Based on clinical trials that included a lower dose of denosumab (the usual dose is 120 mg), patients with a creatinine clearance (CrCl) of less than 30 mL/minute or who were receiving dialysis were at a greater risk of severe hypocalcemia compared with patients with normal renal function. In a trial of 55 patients without cancer and with varying degrees of renal impairment who received a single dose of 60 mg of denosumab, 8 of 17 patients with a CrCl of less than 30 mL/minute or who were receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL compared with 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosage of 120 mg every 4 weeks has not been evaluated in patients whose CrCl is less than 30 mL/minute or who are receiving dialysis.

Osteonecrosis of the jaw. Osteonecrosis of the jaw (ONJ) can occur with denosumab. Signs of ONJ include jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials that enrolled patients with osseous metastasis, 2.2% of patients receiving denosumab developed ONJ after a median exposure of 13 doses. Of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance. In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis (a condition for which denosumab is not approved), ONJ developed in 5.4% of patients after a median exposure of 20 doses.

An oral examination and appropriate preventive dentistry should be performed before denosumab therapy is initiated and periodically during therapy. Patients should be advised about oral hygiene practices. Invasive dental procedures should be avoided during denosumab treatment.

Patients who are thought to have ONJ while they are receiving denosumab should receive care by a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition in these patients.

Atypical femoral fractures. Atypical fractures of the femur have been reported with denosumab. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare. The fractures are transverse or short oblique in orientation without evidence of comminution. The cause has not been established; atypical femoral fractures have also occurred in patients with osteoporosis who have not used antiresorptive agents.

Atypical femoral fractures usually occur with minimal or no trauma to the affected area, and they may be bilateral. Many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. Several reports have noted that patients were also receiving glucocorticoids, such as prednisone, at the time of the fracture.

During treatment with denosumab, patients should be advised to report new or unusual thigh, hip, or groin pain. The pain should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interrupting denosumab therapy should be considered after a risk–benefit assessment.

Dosage and Administration: The recommended dose of denosumab is 120 mg, administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Calcium and vitamin D should be administered as necessary to treat or prevent hypocalcemia.

Commentary: Giant-cell tumor of bone generally occurs in adults between 20 and 40 years of age. In most cases, it does not spread to other parts of the body; however, it destroys normal bone as it grows, causing pain, limited range of motion, and bone fractures. This tumor rarely becomes cancerous.

Denosumab was originally approved as Xgeva by the FDA in November 2010 to prevent fractures when cancer has spread to the bones. Granted an orphan product designation because of its intended use to treat a rare disease, denosumab was approved for its new indication in June 2013 following a priority review by the FDA. This biologic product represents an important advance in the treatment of giant-cell tumor of bone.

Prolia, another form of denosumab, was approved in June 2010. It is used to treat osteoporosis in postmenopausal women who have a high risk of bone fracture.


Brisdelle (Paroxetine Mesylate) Capsules

Manufacturer: Noven Pharmaceuticals, Miami, Fla.

Indication: Paroxetine mesylate has been approved for the treatment of moderate-to-severe hot flashes associated with menopause.

Drug Class: Paroxetine is a selective serotonin reuptake inhibitor (SSRI). This medication is the first FDA-approved nonhormonal therapy for hot flashes (vasomotor symptoms) in women experiencing menopause. It is the mesylate salt of a phenylpiperidine compound and is identified chemically as (-)-trans-4R-(4′-fluorophenyl)–3S–[(3′, 4′-methylenedioxyphenoxy)methyl]piperidine mesylate. The empirical formula is C19H20FNO3 • CH3SO3H, and the molecular weight is 425.5 (329.4 as free base).

Paroxetine mesylate is also sold as Pexeva, and paroxetine HCl is sold as Paxil. Both drugs are used as antidepressants.

Uniqueness of Drug: The effectiveness of paroxetine appears to be linked to the potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin, or 5-hydroxytryptamine (5-HT). In studies of clinically relevant doses in humans, paroxetine blocked the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake; it has only weak effects on norepinephrine and dopamine neuronal reuptake.

Boxed Warning: Paroxetine mesylate and related anti-depressants may increase suicidal thoughts or actions in children and young adults within the first few months of treatment. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Patients should inform their health care practitioner if they notice any sudden changes in mood, behavior, actions, thoughts, or feelings. Patients should also note any changes when they begin taking paroxetine mesylate.

Warnings and Precautions:

Serotonin syndrome. Patients may experience nervousness, hallucinations, coma, or other changes in mental status; loss of coordination; tachycardia; high or low blood pressure; sweating or fever; nausea, vomiting, or diarrhea; muscle rigidity; dizziness; flushing; tremors; or seizures.

Reduced effectiveness of tamoxifen. Tamoxifen, which is used to prevent and treat breast cancer, might not work as well if it is taken at the same time as paroxetine mesylate. Patients should inform their health care professional if they are taking tamoxifen before they start taking paroxetine mesylate.

Abnormal bleeding. Bleeding or bruising may occur, especially if the patient is also taking warfarin or nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, or aspirin.

Low serum sodium levels. Elderly people may be at greater risk for hyponatremia. Symptoms may include headache, weakness, confusion, or difficulty concentrating.

Bone fractures. Women taking paroxetine mesylate may have a higher risk of bone fractures.

Manic episodes. Mania can be manifested as increased energy, trouble sleeping, racing thoughts, reckless behavior, grandiosity, excessive happiness or irritability, and talking more frequently or faster than usual.

Seizures or convulsions. The overall incidence of seizures in patients taking antidepressants at reasonable doses and presumed therapeutic ranges is 0.1% to 4.0%. The incidence is 0.2% for paroxetine, fluoxetine, fluvoxamine, venlafaxine, and sertraline (at the higher doses generally required for obsessive–compulsive disorder).

Restlessness. Patients may feel an inner nervousness or may be unable to sit still or stand still, especially when they start taking paroxetine mesylate.

Visual symptoms. Blurred vision may occur in patients taking paroxetine mesylate.

Dosage and Administration: Each capsule contains 7.5 mg of paroxetine. The capsule is taken once daily at bedtime.

Commentary: Before Brisdelle was approved, hormonal therapy was the only FDA-approved treatment for vasomotor symptoms, which affect up to 75% of women and can persist for 5 years or more. Hot flashes and night sweats are not life-threatening, but symptoms can be bothersome, causing discomfort and disruption of sleep.

Many women are unable or unwilling to take hormone therapy to treat symptoms associated with menopause. At the low dose of 7.5 mg of paroxetine as a mesylate salt, Brisdelle was specifically developed for women in menopause. Brisdelle contains a lower dose of paroxetine than Paxil (paroxetine HCl) and Pexeva (paroxetine mesylate), which are used to treat depression. Brisdelle is expected to be available in pharmacies in November 2013.