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P T. 2010 April; 35(4): 216–218.
PMCID: PMC2873719

Pharmaceutical Approval Update

Marvin M. Goldenberg, PhD, RPh, MS

Liraglutide Subcutaneous Injection (Victoza)

Manufacturer: Novo Nordisk A/S, Bagsvaerd, Denmark

Indication: Liraglutide (recombinant DNA origin) is prescribed as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes mellitus.

Limitations of use. Liraglutide is not indicated for patients with type-1 diabetes mellitus or diabetic ketoacidosis, and it has not been studied in combination with insulin. This product is not recommended as a first-line therapy for patients with diabetes that is inadequately controlled with diet and exercise. Because liraglutide has not been studied sufficiently in patients with a history of pancreatitis, caution in prescribing is recommended for these patients.

Drug Class: As an analogue of human glucagon-like peptide-1 (GLP-1), liraglutide acts as a GLP-1 receptor agonist. The peptide precursor of liraglutide is produced by a process that includes the expression of recombinant DNA in Saccharomyces cerevisiae. The precursor is engineered to be 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor. The molecular weight is 3,751.2 daltons.

Uniqueness of Product: Liraglutide is an acylated human GLP-1 receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7–37). GLP-1 (7–37) represents less than 20% of total circulating endogenous GLP-1. Like GLP-1(7–37), liraglutide activates the GLP-1 receptor, a membrane-bound cell–surface receptor coupled to adenylyl cyclase by the stimulatory G-protein (Gs) in pancreatic beta cells.

Liraglutide increases intracellular cyclic adenosine mono-phosphate (cAMP), leading to the release of insulin in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose–lowering action also involves a delay in gastric emptying.

Boxed Warning: There is a risk of thyroid tumors in rodents at clinically relevant exposures to this drug. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma, in humans.

Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer and in patients with type-2 multiple endocrine neoplasia syndrome (MEN 2). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound would mitigate the risk of thyroid C-cell tumors in humans.

Patients should be counseled regarding the risk and symptoms of thyroid tumors.

Warnings and Precautions:

Risk of thyroid C-cell tumors. In clinical trials, four cases of thyroid C-cell hyperplasia among liraglutide-treated patients and one case in a comparator-treated patient were reported. Calcitonin, a biological marker of medullary thyroid carcinoma, was measured throughout the clinical development program.

Pancreatitis. In clinical trials, seven cases of pancreatitis among liraglutide-treated patients and one case among comparator-treated patients were reported; five patients had acute pancreatitis, and two patients had chronic pancreatitis. In one liraglutide-treated patient, pancreatitis with necrosis resulted in death; however, a causal relationship could not be established.

Use with medications that cause hypoglycemia. Patients receiving liraglutide in combination with an insulin secretagogue, such as a sulfonylurea, may have an increased risk of hypoglycemia.

Macrovascular outcomes. No clinical studies have established conclusive evidence of macrovascular risk reduction with liraglutide or any other antidiabetic drug.

Dosage and Administration: Liraglutide can be administered once daily at any time of day, independently of meals. It can be injected subcutaneously in the abdomen, thigh, or upper arm. The injection site and timing can be changed without a dose adjustment.

For all patients, liraglutide should be initiated with a dose of 0.6 mg/day for one week. The 0.6-mg starting dose is intended to reduce GI symptoms during initial titration and is not effective for glycemic control. After one week at 0.6 mg/day, the dose should be increased to 1.2 mg. If the 1.2-mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. When patients are beginning liraglutide therapy, the prescriber can consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycemia.

Commentary: Novo Nordisk submitted data involving more than 4,000 patients in six studies to regulators. In five of the trials, liraglutide reduced glycosylated hemoglobin (HbA1c) concentrations significantly better than other agents. The comparators included rosiglitazone (Avandia, GlaxoSmithKline); the DPP-4 inhibitor sitagliptin (Januvia, Merck); insulin glargine (Lantus, Sanofi-Aventis); placebo; and exenatide (Lilly/Amylin), the only other GLP-1 available. The LEAD-2 trial was the exception. It compared liraglutide with glimepiride (Amaryl, Sanofi-Aventis) and showed no significant difference in the ability of the two drugs to lower blood glucose levels; however, it strongly highlighted liraglutide’s advantage in weight control.

The launch price of liraglutide for the 1.2-mg dose was $8.03 a day, a relatively high price for an antidiabetic agent.

Source: www.victoza.com/pdf/PI_(1_Column_Format).pdf

Pneumococcal 13-Valent Conjugate Vaccine (Prevnar 13)

Manufacturer: Wyeth, Collegeville, Pa.

Indication: Prevnar 13 vaccine is approved for use in children six weeks through five years of age for the active immunization against invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. This vaccine is also indicated for preventing otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. No data on the vaccine’s efficacy in otitis media are available for serotypes 1, 3, 5, 6A, 7F, and 19A.

Biological Class: Pneumococcal 13-valent conjugate vaccine (diphtheria CRM197 protein) is a sterile suspension of saccharides of the capsular antigens of 13 S. pneumoniae serotypes, individually linked to non-toxic diphtheria CRM197 protein. Each serotype is grown in soy peptone broth. The individual polysaccharides are purified through centrifugation, precipitation, ultrafiltration, and column chromatography.

The polysaccharides are chemically activated to make saccharides, which are directly conjugated by reductive amination to the protein carrier CRM197 to form the glycoconjugate. CRM197 is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae strain C7 (197) grown in a casamino-acid and yeast extract–based medium. CRM197 is purified through ultrafiltration, ammonium sulfate precipitation, and ion-exchange chromatography. The individual glycoconjugates are purified by ultrafiltration and column chromatography and analyzed for saccharide-to-protein ratios, molecular size, free saccharide, and free protein. The individual glycoconjugates are compounded to formulate Prevnar 13.

Uniqueness of Drug: B cells produce antibodies in response to antigenic stimulation via T-dependent and T-independent mechanisms. Prevnar 13, composed of poly-saccharides conjugated to a carrier protein, elicits a T-cell–dependent immune response. Protein carrier-specific T cells provide the signals needed for maturation of the B-cell response and generation of B-cell memory. This type of response induces immune memory and elicits booster responses on re-exposure in infants and young children to pneumococcal polysaccharides.

Warnings and Precautions:

Allergic or other adverse reactions. Before any dose is given to a patient, all precautions should be taken to prevent allergic or any other adverse reactions. This includes a review of the patient’s immunization history for possible sensitivity to the vaccine or similar vaccines and for previous vaccination-related adverse reactions in order to determine the existence of any contraindication to immunization with Prevnar 13 and to allow an assessment of risks and benefits. Epinephrine and other appropriate agents must be available immediately if an acute anaphylactic reaction occurs following the administration of the vaccine.

Limitations of vaccine effectiveness. Prevnar 13 might not protect all individuals receiving the vaccine; it does not protect against S. pneumoniae serotypes that are not in the vaccine or serotypes unrelated to those in the vaccine. This product does not protect against other microorganisms, and it does not treat active infections. Protection against otitis media is expected to be substantially lower than protection against invasive disease. Because otitis media is caused by many organisms other than the seven serotypes of S. pneumoniae included in the indication, protection against all causes of otitis media is expected to be lower than that provided against pneumococcal otitis media caused by these vaccine serotypes. The duration of protection from immunization is not known.

Altered immunocompetence. Data are not available on the safety and effectiveness of Prevnar 13 in children who are at higher risk for invasive pneumococcal disease (such as those with congenital or acquired splenic dysfunction, HIV infection, malignancy, or nephrotic syndrome) or who might have a reduced antibody response to active immunization because of impaired immune responsiveness. Vaccination in high-risk groups should be considered on an individual basis. The use of pneumococcal conjugate vaccine does not replace the use of 23-valent pneumococcal polysaccharide vaccine (PPV23) in children 24 months of age or older with sickle cell disease, asplenia, HIV infection, or chronic illness or who are otherwise immunocompromised.

Premature infants. Apnea has been observed following intramuscular (IM) vaccination in some infants born prematurely. Decisions about when to administer an IM vaccine, including Prevnar 13, to these infants depend on each infant’s medical status and the potential benefits and risks of vaccination.

Dosage and Administration: Prevnar 13 suspension for IM injection is available in 0.5-mL single-dose, prefilled syringes.

Commentary: Invasive pneumococcal disease includes sepsis and bacteremia, meningitis, bacteremic pneumonia, and empyema. A pneumococcal conjugate vaccine that provides coverage against 13 serotypes with the potential to cause life-threatening illnesses is now available for infants and young children in the U.S. These 13 serotypes are responsible for most invasive pneumococcal diseases in the U.S. Notably, serotype 19A is now the most common invasive disease-causing serotype in young children. Prevnar 13 includes the seven serotypes in Prevnar 7 (which was the first pneumococcal conjugate vaccine introduced in 2000) plus six other serotypes.

Prevnar 13 should be given as a four-dose series at 2, 4, 6, and 12 to 15 months of age. Children who have received one or more doses of Prevnar 7 may complete the four-dose immunization series with Prevnar 13. Children 15 months through 5 years of age who have received four doses of Prevnar 7 may receive one dose of Prevnar 13 to elicit immune responses to the six additional serotypes. The immune responses induced by this transition schedule to Prevnar 13 may result in lower antibody concentrations for the six additional serotypes (types 1, 3, 5, 6A, 7F, and 19A), compared with antibody concentrations following four doses of Prevnar 13. The clinical relevance of these lower antibody responses is not known.

Source: www.wyeth.com/content/showlabeling.asp?id=501

Olmesartan Medoxomil (Benicar) for Children

Manufacturer: Daiichi Sankyo, Parsippany, N.J.

Indication: Olmesartan medoxomil is indicated for the treatment of hypertension in children 6 to 16 years of age. It may be used alone or in combination with other antihypertensive agents, such as hydrochlorothiazide.

Drug Class: The prodrug is hydrolyzed to olmesartan during absorption from the gastrointestinal (GI) tract. Olme-sartan is a selective angiotensin (AT1) subtype II receptor antagonist. The product is described chemically as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate.

Uniqueness of Drug: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin–angiotensin system (RAS), with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal re-absorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively preventing the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is therefore independent of the pathways for angiotensin II synthesis.

An AT2 receptor is also present in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor.

Blockade of the RAS with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs that are used to treat hypertension. These drugs also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan medoxomil does not inhibit ACE, it does not affect the response to bradykinin. It is not known whether this difference has clinical relevance.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, thereby reducing blood pressure (BP), but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on BP.

Warnings and Precautions:

Fetal and neonatal morbidity and mortality. Drugs that act directly on the RAS can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in patients who were taking ACE inhibitors. When pregnancy is confirmed, olmesartan should be discontinued as soon as possible. Drugs that act directly on the RAS during the second and third trimesters have been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Hypotension. In patients with an activated renin–angiotensin–aldosterone system (RAAS), such as those with volume or salt depletion (who might be treated with high doses of diuretics), symptomatic hypotension may be anticipated after olmesartan treatment begins. Therapy should be initiated under close medical supervision. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous (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 inhibiting the RAAS, changes in renal function may be anticipated in susceptible individuals who receive olmesartan. In patients whose renal function may depend upon the activity of the RAAS (such as those with severe congestive heart failure), ACE inhibitors and angiotensin receptor antagonists have been associated with oliguria or progressive azotemia, and rarely with acute renal failure or death.

Dosage and Administration: The dosage must be tailored for each patient. For children who can swallow tablets, the usual recommended starting dose of olmesartan is 10 mg once daily for patients who weigh from 20 to 35 kg (44–77 pounds), or 20 mg once daily for patients who weigh 35 kg or more. For patients requiring further reduction in BP after two weeks of therapy, the dose may be increased to a maximum of 20 mg once daily for patients who weigh less than 35 kg or to 40 mg once daily for patients who weigh 35 kg or more. For children who cannot swallow tablets, the same dose can be given in an extemporaneous suspension of an olmesartan and purified water mixture.

Commentary: Approximately 5% of American children (3.6 million) have high BP. The average BP of American children is on the rise, in parallel with the increase in children’s weight. Children who are overweight usually have a higher BP than thinner children. Some children inherit the tendency from one or both parents with hypertension. Elevated BP is more frequent and more severe in African-Americans than in Caucasians. Choices for treating high BP in children can include medications, exercise, diet, or a combination of these, according to the physician’s judgment.

On February 11, 2010, Daiichi Sankyo announced the FDA’s approval of olmesartan for children. This agent was originally approved in 2002 for the treatment of hypertension in adults.

Source: www.benicar.com/pdf/prescribing_information.pdf


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