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Pharmaceutical Approval Update December 2014
Manufacturer: Gilead Sciences, Foster City, California
Date of Approval: October 10, 2014
Indication: Chronic hepatitis C virus (HCV) genotype 1 infection
Drug Class: A fixed-dose combination of ledipasvir, an HCV NS5A inhibitor, and sofosbuvir, an HCV nucleotide analog NS5B polymerase inhibitor
Uniqueness of Drug: Harvoni is a fixed-dose combination of ledipasvir and sofosbuvir, which are direct-acting antiviral agents against HCV.
Warnings and Precautions:
Risk of reduced therapeutic effect due to P-glycoprotein (P-gp) inducers. The concomitant use of ledipasvir/sofosbuvir and P-gp inducers may significantly decrease ledipasvir/sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect, so the use of Harvoni with P-gp inducers is not recommended.
Related products. The use of Harvoni with other products containing sofosbuvir is not recommended.
Dosage and Administration: Harvoni is a two-drug fixed-dose combination product that contains 90 mg of ledipasvir and 400 mg of sofosbuvir in a single tablet. The recommended dosage is one tablet taken orally once daily, with or without food. The recommended treatment duration in patients with HCV genotype 1 varies as follows:
- Treatment-naïve patients with or without cirrhosis: 12 weeks. (Patients with pre-treatment HCV RNA of less than 6 million IU/mL may be considered for an eight-week duration.)
- Treatment-experienced patients without cirrhosis: 12 weeks
- Treatment-experienced patients with cirrhosis: 24 weeks
Commentary: Gilead Sciences has been in the forefront of innovation when it comes to the hepatitis C market. Harvoni is no different, as it represents a cure for a majority of HCV patients with genotype 1 without the requirement of traditional, and painful, injections. This combination product showed cure rates of up to 99.1% and is expected to generate more than $10 billion a year in sales. Although efficacy and projections are extremely positive, criticism continues over the high price tag of $94,500 for a 12-week regimen.
Sources: Harvoni prescribing information,
Manufacturer: Eli Lilly and Company, Indianapolis, Indiana
Date of Approval: September 18, 2014
Indication: Trulicity is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus. It is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC), patients with multiple endocrine neoplasia syndrome type 2, and patients with a prior serious hypersensitivity reaction to dulaglutide or to any of the product’s components.
Drug Class: Glucagon-like peptide-1 (GLP-1) receptor agonist
Uniqueness of Drug: Dulaglutide is a human GLP-1 receptor agonist with 90% amino acid sequence homology to endogenous human GLP-1. Dulaglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase in pancreatic beta cells. Dulaglutide increases intra-cellular cyclic AMP (cAMP) in beta cells, leading to glucose-dependent insulin release. Dulaglutide also decreases glucagon secretion and slows gastric emptying.
Warnings and Precautions:
Risk of thyroid C-cell tumors. GLP-1 receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is not known whether dulaglutide will cause thyroid C-cell tumors (including MTC) in humans, as the human relevance of this signal could not be determined from the clinical or nonclinical studies.
Pancreatitis. After initiation of dulaglutide, observe patients carefully for signs and symptoms of pancreatitis, including persistent, severe abdominal pain. If pancreatitis is suspected, promptly discontinue dulaglutide. If pancreatitis is confirmed, dulaglutide should not be restarted. Dulaglutide has not been evaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
Hypoglycemia with concomitant use of insulin secretagogues or insulin. The risk of hypoglycemia is increased when dulaglutide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting.
Hypersensitivity reactions. If a hypersensitivity reaction occurs, the patient should discontinue dulaglutide and promptly seek medical advice.
Renal impairment. In patients treated with GLP-1 receptor agonists, there have been post-marketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Use caution when initiating or escalating doses of dulaglutide in patients with renal impairment. Monitor renal function in patients with renal impairment who report severe adverse gastrointestinal reactions.
Severe gastrointestinal disease. Use of dulaglutide may be associated with gastrointestinal adverse reactions, sometimes severe. Dulaglutide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is not recommended in these patients.
Macrovascular outcomes. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with dulaglutide or any other antidiabetic drug.
Dosage and Administration: The recommended initiating dose of Trulicity is 0.75 mg once weekly. The dose may be increased to a maximum of 1.5 mg once weekly for additional glycemic control.
Administer Trulicity once weekly, at any time of day, with or without food. The medication should be injected subcutaneously in the abdomen, thigh, or upper arm. If a dose is missed, instruct patients to administer it as soon as possible if at least three days (72 hours) remain until the next scheduled dose. If less than three days remain before the next scheduled dose, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once-weekly dosing schedule.
Commentary: Trulicity was approved after results from six clinical trials showed a reduction in blood sugar levels. As another medication used to treat type-2 diabetes, this drug will compete with the other GLP-1 drugs already approved in this space. Trulicity hopes to gain popularity as a once-weekly injection, but it will face competition because other once-weekly injections already exist. The Food and Drug Administration is requiring that Lilly perform various post-marketing studies to evaluate certain endpoints and is also requiring a risk evaluation and mitigation strategy (REMS) to inform health care professionals about the serious risks associated with the drug.
Manufacturer: Eisai Inc., Woodcliff Lake, New Jersey
Date of Approval: October 10, 2014
Indication: Akynzeo is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.
Drug Class: Netupitant is a substance P/neurokinin 1 (NK1) receptor antagonist, and palonosetron is a serotonin-3 (5-HT3) receptor antagonist.
Uniqueness of Drug: Netupitant is a selective antagonist of human substance P/NK1 receptors. Delayed emesis has been largely associated with the activation of tachykinin family NK1 receptors (broadly distributed in the central and peripheral nervous systems) by substance P. Netupitant has been shown to inhibit substance P–mediated responses in studies.
Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Chemotherapy agents produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. The development of acute emesis is known to depend on serotonin, and its 5-HT3 receptors have been demonstrated to selectively stimulate the emetic response. Palonosetron works by antagonizing the 5-HT3 receptor.
Warnings and Precautions:
Hypersensitivity. Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hyper-sensitivity to other 5-HT3 receptor antagonists.
Serotonin syndrome. The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), and seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of netupitant/palonosetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Akynzeo and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Akynzeo is used concomitantly with other serotonergic drugs.
Dosage and Administration: With highly emetogenic chemotherapy (including cisplatin-based chemotherapy), the recommended dosage in adults is one capsule of Akynzeo administered approximately one hour prior to the start of chemotherapy, with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1 and 8 mg orally once daily on days 2 to 4.
With anthracyclines and cyclophosphamide-based chemotherapy and chemotherapy not considered highly emetogenic, the recommended dosage in adults is one capsule of Akynzeo approximately one hour prior to the start of chemotherapy, with dexamethasone 12 mg administered orally 30 minutes prior to chemotherapy on day 1. Administration of dexamethasone on days 2 to 4 is not necessary.
Akynzeo can be taken with or without food.
Commentary: Chemotherapy agents are typically associated with severe nausea and vomiting that occurs after drug administration. Agents are developed to aid patients in managing this adverse event to ensure administration is not discouraged. Akynzeo is a combination product that has been developed utilizing palonosetron to prevent early vomiting and netupitant to treat chemo-related nausea and nausea that occurs later. It was approved with the results of clinical trials in which up to 98.5% of patients did not experience any vomiting or require nausea medications.
Sources: Akynzeo prescribing information,
Manufacturer: AstraZeneca Pharmaceuticals LP, Wilmington, Delaware
Date of Approval: September 16, 2014
Indication: Movantik is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic noncancer pain. It is contraindicated in:
- Patients with known or suspected gastrointestinal (GI) obstruction and patients at increased risk of recurrent obstruction, due to the potential for GI perforation
- Patients concomitantly using strong CYP3A4 inhibitors because these medications significantly increase exposure to naloxegol, which may precipitate opioid withdrawal symptoms
- Patients who have had a known serious or severe hyper-sensitivity reaction to naloxegol
Drug Class: Opioid antagonist
Uniqueness of Drug: Naloxegol is an antagonist of opioid binding at the mu-opioid receptor. When administered at the recommended dose levels, naloxegol functions as a peripherally acting mu-opioid receptor antagonist in tissues such as the GI tract, thereby decreasing the constipating effects of opioids.
Warnings and Precautions:
Gastrointestinal perforation. Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue naloxegol in patients who develop this symptom.
Opioid withdrawal. Monitor for symptoms of opioid withdrawal in patients receiving naloxegol. Symptoms consistent with opioid withdrawal may include hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Dosage and Administration: The recommended dosage is 25 mg once daily in the morning. If patients are unable to tolerate naloxegol, the dose should be reduced to 12.5 mg once daily.
Naloxegol should be taken on an empty stomach at least one hour prior to the first meal of the day or two hours after the meal. Naloxegol has been shown to be efficacious in patients who have taken opioids for at least four weeks. Discontinue all maintenance laxative therapies prior to initiating the medication; laxatives may be continued if a suboptimal response is observed after three days. No alteration in analgesia is required prior to initiating naloxegol.
Commentary: Movantik, the first mu-opioid antagonist approved specifically for opioid-induced constipation (OIC), has beaten all rival pills to market. Although other opioid antagonists are available, this is the first pill formulation approved for OIC, which will be preferred by patients over injectable and off-label medications. The drug is expected to be successful in today’s market, but extensive awareness campaigns will be required to educate patients and health care professionals on the importance of OIC treatments such as Movantik.