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Pharmaceutical Approval Update March 2012

Marvin M. Goldenberg PhD, RPh, MS

Extended-Release Exenatide For Injectable Suspension (Bydureon)

Manufacturer: Amylin Pharmaceuticals, San Diego, Calif.

Indication: Bydureon, administered once weekly as a subcutaneous (SQ) injection, is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type-2 diabetes mellitus.

Drug Class: Exenatide is a synthetic hormone and an incretin mimetic derived from the saliva of the Gila monster, a poisonous lizard in the southwestern U.S. and Mexico.

Uniqueness of Drug: As a glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide mimics the effect of glucagon-like peptide-1, a hormone that increases insulin production when blood glucose levels are high. Insulin is slowly released in the body after injection. Byetta (Amylin/Eli Lilly), which is injected twice daily, was the first GLP-1 receptor agonist to be approved by the FDA for patients with type-2 diabetes mellitus. Bydureon is a long-acting form of the medication in Byetta (exenatide) injection; therefore, both drugs should not be used together.

Boxed Warning:

Risk of thyroid C-cell tumors. Extended-release exenatide causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats when compared with controls. It is unknown whether Bydureon causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans; relevance to humans was not able to be determined by clinical or nonclinical studies. Bydureon is contraindicated in patients with a personal or family history of MTC and in patients with type-2 multiple endocrine neoplasia syndrome (MEN-2). Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients who receive Bydureon. Patients should be counseled about the risk of thyroid tumors and their associated symptoms.

Warnings and Precautions:

Pancreatitis. Based on postmarketing data, exenatide has been associated with acute pancreatitis, fatal and nonfatal hemorrhagic pancreatitis, and necrotizing pancreatitis. After initiation of therapy, patients should be carefully observed for the presence of pancreatitis. Symptoms include persistent, severe abdominal pain that sometimes radiates to the back, with or without vomiting. If pancreatitis is suspected, Bydureon should be discontinued promptly. If pancreatitis is confirmed, therapy should not be restarted.

Hypoglycemia. There is an increased risk of hypoglycemia when Bydureon is used with glucose-independent insulin secretagogues (e.g., sulfonylureas). Clinicians may consider reducing the sulfonylurea dose.

Renal impairment. Bydureon should not be prescribed for patients with severe renal impairment or end-stage renal disease. It should be used with caution in renal transplant recipients or in patients with moderate renal failure. Post-marketing reports have mentioned altered renal function with exenatide, including increased serum creatinine levels, renal impairment, worsening chronic renal failure, and acute renal failure, with hemodialysis and kidney transplantation sometimes required.

Gastrointestinal disease. Patients with severe gastrointestinal disease, such as gastroparesis, should not receive Bydureon.

Antibodies. Patients may develop antibodies to exenatide. In five registration trials, 6% of Bydureon-treated patients experienced an attenuated glycemic response accompanied by antibody formation. An alternative antidiabetic therapy should be considered if adequate glycemic control is not achieved, if it worsens, or if it fails.

Hypersensitivity. Serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) have been reported. If these reactions occur, patients should discontinue therapy or other suspected medications and should promptly seek medical advice.

Vascular events. No clinical studies have shown conclusive evidence of macrovascular risk reduction with Bydureon or with any other antidiabetic drug.

Dosage and Administration: The recommended dose of Bydureon is 2 mg once weekly on the same day each week. The day of the week can be changed, if necessary, as long as the next dose is administered at least one day later.

When Bydureon is added to existing metformin (Glucophage, Bristol-Myers Squibb) and/or thiazolidinedione therapy, the current metformin thiazolidinedione regimen can be continued. When Bydureon is added to a sulfonylurea, a reduced sulfonylurea dose should be considered to decrease the risk of hypoglycemia. No dose adjustments are required based on age, moderate renal impairment, or hepatic impairment.

Bydureon is intended for self-administration by the patient. Each SQ dose is injected into the abdomen, thigh, or back of upper arm.

Commentary: Bydureon is an injectable, once-weekly extended-release version of Amylin’s older diabetes drug, Byetta. Both drugs share an active ingredient, exenatide, which promotes the production of insulin.

In the DURATION-5 clinical trial, after 6 months Bydureon reduced glycosylated hemoglobin (HbA1c) levels by 1.6 percentage points from baseline, compared with a 0.9-percentage point reduction with Byetta. At the end of the study, patients using Bydureon lost an average of 5.1 pounds; Byetta patients lost an average of 3.0 pounds. Bydureon patients also reported less nausea than Byetta patients.

Bydureon is entering the market with a price tag of $323 for a month’s supply, which costs less than the $421 charged by Novo Nordisk for the same supply of liraglutide (Victoza), a once-daily injectable agent that may help improve blood glucose levels in adults with type-2 diabetes. However, in an Amylin-sponsored head-to-head study last year, liraglutide brought about better glycemic control than Bydureon. Another advantage of liraglutide is the smaller size of the needles required for injections. Yet Amylin might be able to prevail with patients and doctors who view the less frequent injection schedule as their best chance for glycemic control, as poor adherence has been a major problem in treating diabetes.

Bydureon was approved with a Risk Evaluation and Mitigation Strategy (REMS).

Sources: Amylin/Alkermes,, January 27, 2012;, January 29, 2012; The New York Times, January 28, 2012;

Clobazam Tablets (Onfi)

Manufacturer: Lundbeck/Catalent, Deerfield, Ill.

Indication: Clobazam, an antiepileptic drug, is indicated for the adjunctive treatment of seizures associated with Lennox–Gastaut syndrome in patients 2 years of age or older.

Drug Class: The chemical name of clobazam, a benzodiazepine, is 7-chloro-1-methyl-5-phenyl-1H-1,5 benzodiazepine-2,4(3H,5H)-dione. Clobazam is a Schedule IV medication.

Uniqueness of Drug: Clobazam’s exact mechanism of action is not fully understood, but it is thought to involve the potentiation of gamma-aminobutyric acid (GABA)-ergic neuro-transmission resulting from binding at the benzodiazepine site of the GABA-A receptor.

Warnings and Precautions:

Somnolence or sedation. In clinical trials, somnolence or sedation was reported at all effective doses. In general, these dose-related effects begin within the first month of therapy and may diminish with continued treatment. Health care practitioners and prescribers should monitor patients for somnolence and sedation, particularly with the concomitant use of other central nervous system (CNS) depressants. Patients should be cautioned against participating in activities that call for mental alertness (e.g., operating machinery or motor vehicles) until the effect of clobazam is known.

Concomitant use with CNS depressants. Because clobazam has a depressant effect on the CNS, patients or their caregivers should be cautioned against its simultaneous use with other CNS depressant drugs or alcohol. Patients should be advised that the effects of other CNS depressant drugs or alcohol might be increased when both drugs are used concomitantly.

Withdrawal. Clobazam therapy should not be stopped abruptly; the dose should be tapered downward every week by 5 to 10 mg/day until discontinuation is complete. Withdrawal symptoms have occurred following the abrupt discontinuation of clobazam, and the risk of these symptoms is greater with higher doses. As with all antiepileptic drugs, clobazam should be withdrawn gradually to minimize the risk of precipitating or exacerbating seizures and to reduce the risk of status epilepticus.

Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorders, tremor, and anxiety) have been reported following the abrupt cessation of benzodiazepine treatment. The more severe symptoms have usually been limited to patients who received excessive doses over an extended period of time, followed by an abrupt discontinuation of therapy. Generally milder symptoms, including dysphoria, anxiety, and insomnia, have been reported following the abrupt discontinuance of benzodiazepines that have been taken continuously at therapeutic doses for several months.

Physical and psychological dependence. Patients with a history of substance abuse should be carefully monitored during therapy with clobazam or other psychotropic agents because of the predisposition of these patients to habituation and dependence.

Suicidal behavior and ideation. Antiepileptic agents, including clobazam, have been found to increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients who are using these medications should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. The increased risk of suicidal thoughts or behavior with this drug class was observed as early as 1 week after the start of therapy, persisted for the duration of treatment, and was generally consistent among drugs analyzed. The finding of an increased risk with antiepileptic drugs of varying mechanisms of action and for a range of indications suggests that the risk applies to all drugs in this class used for any indication. The risk did not vary substantially by patients’ ages (range, 5–100 years) in the trials analyzed.

Dosage and Administration: Each tablet contains 5 mg, 10 mg, or 20 mg of clobazam. The tablets should be taken in divided doses twice daily. The 5-mg dose can be taken as a single daily dose. Doses should vary according to body weight; within each weight-based group of patients, doses should be individualized according to clinical efficacy and tolerability. All doses in Table 1 have been effective, although their effectiveness increases with each increase in dosage. Dose escalation should not proceed more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady state.

Clobazam tablets may be swallowed whole, or they may be crushed and mixed in applesauce. The medication may be taken without regard to timing of meals.

Geriatric patients. Plasma concentrations of all doses of clobazam are generally higher in the elderly, and dose escalation should proceed slowly. The starting dose is 5 mg/day for all elderly patients. The dose should then be titrated upward according to weight, but to half the dose as presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 or 40 mg/day, depending on weight) may be started on day 21.

Poor metabolizers of cytochrome P450 2C19. In patients who are poor metabolizers of CYP2C19, levels of N-desmethyl-clobazam, the drug’s active metabolite, are increased. Therefore, in patients who are known to be poor CYP2C19 metabolizers, the starting dose should be 5 mg/day. Dose titration should proceed slowly according to the patient’s weight, but to half the dose shown in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 or 40 mg/day, depending on the weight group) may be started on day 21.

Patients with renal impairment. No dosage adjustments of clobazam are required for patients with mild or moderate renal impairment. Data regarding patients with severe renal impairment or end-stage renal disease (ESRD) are not available. It is not known whether clobazam or its active metabolite, N-desmethylclobazam, is dialyzable.

Patients with hepatic impairment. Clobazam is metabolized by the liver, but data regarding the effect of hepatic impairment on the drug’s pharmacokinetics are limited. For this reason, dose titration should proceed slowly. For patients with mild-to-moderate hepatic impairment (Child–Pugh score, 5–9), the starting dose should be 5 mg/day in both weight groups. The dose should then be titrated upward according to the patient’s weight, but to half the dose (see Table 1), as tolerated. If necessary, and based upon the patient’s response, an additional titration to the maximum dose (20 or 40 mg/day, depending on weight) may be started on day 21. Information about the metabolism of clobazam in patients with severe hepatic impairment is lacking; therefore, no dosing recommendations for those patients can be given.

Commentary: The FDA approved clobazam as an orphan drug to be used as adjunctive therapy for seizures associated with Lennox–Gastaut syndrome in patients 2 years of age and older. This rare, severe form of epilepsy is typically diagnosed in childhood.

The FDA’s approval was based on two studies, including a phase 3 trial involving 238 patients with a current or previous diagnosis of Lennox–Gastaut syndrome. In the latter group, high doses of clobazam decreased weekly seizures by an average of 68% compared with placebo. The FDA, which also granted Lundbeck a 7-year exclusivity period, noted that clobazam might slow thinking and impair motor skills. It is therefore important that patients who take clobazam do not drive, operate heavy machinery, or engage in other similar dangerous activities until they know how the drug affects them.

Patients should report any worsening symptoms (e.g., mood or behavior changes, anxiety, panic attacks, trouble sleeping, impulsivity, irritability, agitation, hostility, aggressiveness, restlessness, mental or physical hyperactivity, depression, or suicidal thoughts). Clobazam should be kept in a secure place. A medication guide is required for patients and their caregivers.

Sources: FDA, October 24, 2011;

Glucarpidase Injection (Voraxaze)

Manufacturer: BTG International, Inc., West Conshohocken, Pa.

Indication: Glucarpidase helps to eliminate excessively high levels of methotrexate (MTX) in patients whose kidney function has been impaired by treatment with high doses of this chemotherapeutic agent. MTX is normally eliminated from the body by the kidneys, but prolonged high doses, when used to treat cancer, can cause kidney failure. Glucarpidase injection quickly breaks down MTX and allows the body to excrete it.

Drug Class: Glucarpidase is a carboxypeptidase enzyme produced by recombinant DNA technology in genetically modified Escherichia coli. This 390-amino acid homodimer protein has a molecular weight of 83 kilodaltons. Each protein unit corresponds to the enzymatic cleavage of 1 micromole/L of MTX per minute at 37°C.

Uniqueness of Drug: As a recombinant bacterial enzyme, glucarpidase hydrolyzes the carboxyl terminal glutamate residue from folic acid and classical antifolates such as MTX. It converts MTX to its inactive metabolite, 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA), and glutamate. Leucovorin calcium (Immunex Corp.) provides an alternate non-renal pathway for MTX elimination in patients with renal dysfunction during high-dose MTX treatment.

Warnings and Precautions:

Allergic reactions. Serious allergic reactions have occurred in fewer than 1% of patients who have received glucarpidase.

Monitoring methotrexate. Within 48 hours after the administration of glucarpidase, chromatography is the only reliable way to measure MTX levels. DAMPA, an inactive metabolite of MTX resulting from glucarpidase therapy, interferes with the ability to obtain accurate MTX levels. The use of an immunoassay results in an overestimate of MTX levels. Because of the long half-life of DAMPA (9 hours), therefore, measurements of MTX using immunoassays are unreliable for samples collected within 48 hours after patients receive glucarpidase.

Leucovorin rescue. Leucovorin is continued after glucarpidase is administered, but leucovorin should not be given within 2 hours before or after a dose of glucarpidase because it is a substrate for glucarpidase. For the first 48 hours after glucarpidase is given, the same leucovorin dose is administered as before glucarpidase. Beyond 48 hours after the glucarpidase dose, leucovorin is administered according to the measured MTX level. Leucovorin therapy should not be discontinued based on a determination of a single MTX concentration below the leucovorin treatment threshold. Leucovorin should be continued until the MTX level is maintained below the leucovorin treatment threshold for a minimum of 3 days. Hydration and alkalinization of the urine should be continued as indicated.

Dosage and Administration: Glucarpidase is supplied as a sterile, preservative-free, lyophilized powder in single-use vials. The recommended dose is a single IV bolus injection of 50 units/kg, given over a period of 5 minutes. The IV line should be flushed before and after the administration of glucarpidase.

Commentary: Prolonged exposure to high levels of MTX can result in kidney and liver injury, severe mouth sores, damage to the intestinal lining, skin rashes, and death attributable to low blood counts. In a clinical trial of 22 patients, glucarpidase eliminated 95% of MTX from the blood. For 10 patients, the MTX dropped to a low level within 15 minutes and stayed that way for 8 days. Glucarpidase represents an important new option for cancer patients with the aim of preventing these toxicities associated with sustained high levels of MTX.

Glucarpidase was granted orphan drug status by the FDA.

Sources: FDA and Reuters, January 17, 2012


Recommended Total Daily Dosing of Clobazam by Patient Weight Group

30 kg or Less Of Body Weight More Than 30 kg Of Body Weight
Starting dose 5 mg 10 mg
Starting day 7 10 mg 20 mg
Starting day 14 20 mg 40 mg