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Pharmaceutical Approval Update November 2016
Manufacturer: OPKO Health, Inc., Miami, Florida
Date of Approval: June 17, 2016
Indication: Calcifediol is indicated for the treatment of secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease (CKD) and serum total 25-hydroxyvitamin D levels less than 30 ng/mL. Calcifediol is not intended for use in patients with stage 5 CKD or with end-stage renal disease receiving dialysis.
Drug Class: Vitamin D analogue
Uniqueness of Drug: Stage 3 and 4 CKD patients are treated with high-dose vitamin D supplements with arguable efficacy. Calcifediol is the first drug approved to treat SHPT in predialysis patients. It is a prohormone formulated as an extended-release capsule containing 30 mcg of the medication. Calcifediol raises serum total 25-hydroxyvitamin D levels and lowers elevated intact parathyroid hormone (iPTH) levels.
Warnings and Precautions:
Hypercalcemia. Excessive administration of vitamin D compounds, including calcifediol, can cause hypercalcemia and hypercalciuria. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention. Patients should be informed about the symptoms of elevated serum calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, and weight loss.
Digitalis toxicity. Hypercalcemia increases the risk of digitalis toxicity. In patients using calcifediol concomitantly with digitalis compounds, monitor both the serum calcium level and the patient for signs and symptoms of digitalis toxicity and increase the frequency of monitoring when initiating or adjusting the calcifediol dose.
Adynamic bone disease. Adynamic bone disease with subsequent increased risk of fractures may develop if iPTH levels are suppressed by calcifediol to abnormally low levels. Monitor iPTH levels and adjust dose if needed.
Dosage and Administration: The initial dose of calcifediol is 30 mcg administered orally once daily at bedtime. Ensure serum calcium is lower than 9.8 mg/dL before initiating treatment. The maintenance dose should target serum total 25-hydroxy-vitamin D levels between 30 and 100 ng/mL, iPTH levels within the desired therapeutic range, serum calcium (corrected for low albumin) within the normal range, and serum phosphorus lower than 5.5 mg/dL. Monitor serum calcium, phosphorus, 25-hydroxyvitamin D, and iPTH levels three months after starting therapy or changing dose. Increase the dose to 60 mcg once daily after three months if iPTH is greater than the treatment goal. Ensure serum calcium is lower than 9.8 mg/dL, phosphorus is lower than 5.5 mg/dL, and 25-hydroxyvitamin D is lower than 100 ng/mL before increasing the dose. Suspend dosing if iPTH is persistently abnormally low, serum calcium is consistently above the normal range, or serum 25-hydroxyvitamin D is consistently greater than 100 ng/mL.
Commentary: Two double-blind, randomized, dose-ranging, placebo-controlled clinical trials have met all primary efficacy and safety endpoints. At 26 weeks, treatment with calcifediol achieved at least a 30% reduction in plasma iPTH in patients with stage 3 or 4 CKD with SHPT and vitamin D insufficiency, compared with those treated with placebo. More than 80% of patients treated with calcifediol saw their vitamin D insufficiency corrected compared with fewer than 7% of patients treated with the placebo.
Sources: OPKO Health, Inc., Rayaldee prescribing information
Dasabuvir/Ombitasvir/Paritaprevir/Ritonavir (Viekira XR)
Manufacturer: AbbVie, Inc., North Chicago, Illinois
Date of Approval: July 22, 2016
Indication: Viekira XR is indicated for the treatment of adult patients with chronic hepatitis C virus (HCV) infection of two specific genotypes: 1) genotype 1b without cirrhosis or with compensated cirrhosis and 2) genotype 1a without cirrhosis or with compensated cirrhosis for use in combination with ribavirin.
Drug Class: HCV non-nucleoside nonstructural protein (NS) 5B palm polymerase inhibitor (dasabuvir), HCV NS5A inhibitor (ombitasvir), HCV NS3/4A protease inhibitor (paritaprevir), and cytochrome P450 (CYP) 3A inhibitor (ritonavir)
Uniqueness of Drug: Viekira XR is the first coformulated treatment combining three direct-acting HCV antiviral agents with distinct mechanisms of action for adult patients with genotype 1 HCV. Although ritonavir is not active against HCV, it is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of paritaprevir and overall drug exposure (i.e., area under the curve). Of the six major HCV genotypes, genotype 1 is the most prevalent form of HCV in the U.S., accounting for approximately 74% of all cases.
Warnings and Precautions:
Hepatic decompensation and hepatic failure in patients with cirrhosis. Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported mostly in patients with advanced cirrhosis. Viekira XR is contraindicated in patients with moderate-to-severe hepatic impairment (Child–Pugh B and C). For patients with cirrhosis:
- Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, or variceal hemorrhage).
- Hepatic laboratory testing, including direct bilirubin levels, should be performed at baseline and during the first four weeks of treatment and as clinically indicated.
- Discontinue Viekira XR in patients who develop evidence of hepatic decompensation.
Alanine aminotransferase (ALT) elevations. Discontinue ethinyl estradiol-containing medications prior to starting Viekira XR (alternative contraceptive methods are recommended). Perform hepatic laboratory testing on all patients during the first four weeks of treatment and as clinically indicated thereafter. If ALT is found to be elevated above baseline levels, testing should be repeated and monitored closely. Consider discontinuing Viekira XR if ALT levels remain persistently greater than 10 times the upper limit of normal. Discontinue treatment if ALT elevation is accompanied by signs or symptoms of liver inflammation or increasing direct bilirubin, alkaline phosphatase, or international normalized ratio.
Risks associated with ribavirin combination treatment. If Viekira XR is administered with ribavirin, the warnings and precautions for ribavirin also apply to this combination regimen.
Drug interactions. The concomitant use of Viekira XR and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of Viekira XR. Consult the full prescribing information for the complete list.
Dosage and Administration: Prior to initiation of therapy, assess for laboratory and clinical evidence of hepatic decompensation. The recommended dosage is three tablets taken once daily with a meal for the duration of treatment (
Commentary: The components of Viekira XR were studied in seven phase 3 clinical trials in which more than 2,000 patients received the components of Viekira XR with or without ribavirin for 12 or 24 weeks. A sustained viral response 12 or more weeks past the end of treatment was achieved in 95% to 100% of patients, meaning the virus was no longer detectable in their blood. Cure rates depended on the subtype of HCV and whether the person had cirrhosis.
Sources: AbbVie, Inc., Viekira XR prescribing information
Manufacturer: Sanofi-Aventis, Bridgewater, New Jersey
Date of Approval: July 27, 2016
Indication: Lixisenatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus. It has not been studied in patients with chronic pancreatitis or a history of unexplained pancreatitis. It is not approved for the treatment of type-1 diabetes or diabetic ketoacidosis and has not been studied in combination with short-acting insulin. Lixisenatide has not been studied in patients with gastroparesis.
Drug Class: Glucagon-like peptide-1 (GLP-1) receptor agonist
Uniqueness of Drug: GLP-1 is a peptide hormone that is released within minutes of eating a meal. It is known to suppress glucagon secretion from pancreatic alpha cells and stimulate glucose-dependent insulin secretion by pancreatic beta cells. Lixisenatide increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying. Lixisenatide is already approved in more than 60 countries worldwide and marketed in over 40 under a different brand name.
Warnings and Precautions:
Anaphylaxis and serious hypersensitivity reactions. Closely monitor patients with a history of anaphylaxis or angioedema with other GLP-1 receptor agonists for allergic reactions to lixisenatide; it is unknown whether these patients will be predisposed to anaphylaxis with this agent. If a hypersensitivity reaction occurs, the patient should discontinue the medication and promptly seek medical attention.
Pancreatitis. Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been reported post-marketing in patients treated with GLP-1 receptor agonists. If pancreatitis is suspected, promptly discontinue the medication and initiate appropriate management. If pancreatitis is confirmed, do not restart therapy. Consider other antidiabetic therapies in patients with a history of pancreatitis.
Never share lixisenatide pens between patients. Lixisenatide pens should never be shared between patients, even if the needle is changed. Pen sharing poses a risk for transmission of blood-borne pathogens.
Hypoglycemia and concomitant use of sulfonylurea or basal insulin. When lixisenatide is used with a sulfonylurea or basal insulin, consider lowering the dose of the sulfonylurea or basal insulin to reduce the risk of hypoglycemia.
Acute kidney injury. Monitor renal function in patients with renal impairment who report severe adverse gastrointestinal reactions. Lixisenatide is not recommended in patients with end-stage renal disease.
Immunogenicity. Patients may develop antibodies to lixisenatide. If there is worsening glycemic control or failure to achieve targeted glycemic control, significant injection-site reactions or allergic reactions, alternative antidiabetic therapy should be considered
Macrovascular outcomes. Clinical studies have not shown macrovascular risk reduction with lixisenatide or any other antidiabetic drug.
Dosage and Administration: The starting dose of lixisenatide is 10 mcg subcutaneously once daily for 14 days. Increase the dose to the maintenance dose of 20 mcg once daily starting on day 15. Instruct patients and caregivers on the preparation and use of the pen prior to first use of lixisenatide. Training should include a practice injection. Administer lixisenatide by subcutaneous injection in the abdomen, thigh, or upper arm once daily. Rotate injection sites with each dose. Instruct patients to administer an injection of lixisenatide one hour before the first meal of the day, preferably the same meal each day. If a dose is missed, administer within one hour prior to the next meal. Instruct patients to protect the pen from light by keeping it in its original packaging and to discard it 14 days after its first use.
Commentary: The Food and Drug Administration (FDA) approval of lixisenatide was based on the review of results from the GetGoal clinical program and findings from the ELIXA trial, which successfully addressed the FDA’s request to demonstrate cardiovascular safety. The GetGoal clinical program, which included 13 clinical trials involving more than 5,000 adults with type-2 diabetes worldwide, evaluated the safety and efficacy of lixisenatide. All studies of the GetGoal program successfully met the primary efficacy endpoint of hemoglobin A1c reduction. The most common adverse events reported for lixisenatide included nausea, hypoglycemia, and vomiting.
Sources: Sanofi-Aventis, Adlyxin prescribing information
Viekira XR Treatment Regimen and Duration by Patient Population
|Genotype 1a, without cirrhosis||Viekira XR + ribavirin||12 weeks|
|Genotype 1a, with compensated cirrhosis||Viekira XR + ribavirin||24 weeks|
|Genotype 1b, with or without compensated cirrhosis||Viekira XR||12 weeks|
*Viekira XR + ribavirin for 12 weeks may be considered for some patients based on prior treatment history.