Novel Drug Approvals for 2015

1.Name       -  PRALUENT

2. Active Ingredient-     Airocumab

3. Indication-      To treat certain patients with high cholesterol

Date of Approval     July  2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use PRALUENT safely and effectively. See full prescribing information for PRALUENT. PRALUENTTM (alirocumab) injection, for subcutaneous use

Initial U.S. Approval: 2015 -

INDICATIONS AND USAGE-

 PRALUENT is a PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) inhibitor antibody indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-cholesterol (LDL-C).

 Limitations of Use • The effect of PRALUENT on cardiovascular morbidity and mortality has not been determined.usly once every 2 weeks, since the majority of patients achieve sufficient LDL-C reduction with this dosage. If the LDL-C response is inadequate, the dosage may be increased to the maximum dosage of 150 mg administered every 2 weeks.

 Measure LDL-C levels within 4 to 8 weeks of initiating or titrating PRALUENT, to assess response and adjust the dose, if needed.

ADVERSE REACTIONS-

 The most commonly occurring adverse reactions (=5% of patients treated with PRALUENT and occurring more frequently than with placebo) are nasopharyngitis, injection site reactions, and influenza.

CONTRAINDICATIONS-

 History of a serious hypersensitivity reaction to PRALUENT.

WARNINGS AND PRECAUTIONS-

 • Allergic Reactions: Hypersensitivity reactions (e.g., pruritus, rash, urticaria), including some serious events (e.g., hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization), have been reported with PRALUENT treatment. If signs or symptoms of serious allergic reactions occur, discontinue treatment with PRALUENT, treat according to the standard of care, and monitor until signs and symptoms resolve. 

DOSAGE FORMS AND STRENGTHS-

 • Injection: 75 mg/mL or 150 mg/mL solution in a single-dose pre-filled pen

 • Injection: 75 mg/mL or 150 mg/mL solution in a single-dose pre-filled syringe

PATIENT COUNSELING INFORMATION -

See FDA-Approved Patient Labeling (Patient Information and Instructions for Use).

Allergic Reactions • Advise patients to discontinue PRALUENT and seek prompt medical attention if any signs or symptoms of serious allergic reactions occur.

Instructions for Administration • Instruct patients and caregivers to read the Patient Information and Instructions For Use (IFU) before the patient starts using PRALUENT, and each time the patient gets a refill as there may be new information they need to know.

• Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the pre-filled pen or pre-filled syringe correctly (see Instructions for Use leaflet). Inform patients that it may take up to 20 seconds to inject PRALUENT.

• The pre-filled pen or pre-filled syringe should be allowed to warm to room temperature for 30 to 40 minutes prior to use. PRALUENT should be used as soon as possible after it has warmed up.

Time out of refrigeration should not exceed 24 hours at 77°F (25°C).

• Patients and caregivers should be cautioned that the pre-filled pen or pre-filled syringe must not be re-used and instructed in the technique of proper pen and syringe disposal in a puncture-resistant container. Do not recycle the container.

Manufactured by: 15 Reference ID: 3797282 sanofi-aventis U.S. LLC Bridgewater, NJ 08807, A SANOFI COMPANY U.S. License # 1752 Marketed by sanofi-aventis U.S. LLC, (Bridgewater, NJ 08807) and Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591) PRALUENT is a trademark of Sanofi ©2015 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC Issue Date: July 2015

CLINICAL PHARMACOLOGY

1. Mechanism of Action-

btilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.

2. Pharmacodynamics Alirocumab reduced free PCSK9 in a concentration-dependent manner. Following a single subcutaneous administration of alirocumab 75 or 150 mg, maximal suppression of free PCSK9 occurred within 4 to 8 hours. Free PCSK9 concentrations returned to baseline when alirocumab concentrations decreased below the limit of quantitation.

.3 Pharmacokinetics -                                                                                                     - Absorption -                                                                                                                       After subcutaneous (SC) administration of 75 mg to 150 mg alirocumab, median times to maximum serum concentrations (tmax) were 3-7 days. The pharmacokinetics of alirocumab after single SC administration of 75 mg into the abdomen, upper arm, or thigh were similar.

The absolute bioavailability of alirocumab after SC administration was about 85% as determined by population pharmacokinetics analysis. A slightly greater than dose proportional increase was observed, with a 2.1- to 2.7-fold increase in total alirocumab concentrations for a 2-fold increase in dose. Steady state was reached after 2 to 3 doses with an accumulation ratio of about 2-fold

Distribution- Following IV administration, the volume of distribution was about 0.04 to 0.05 L/kg indicating that alirocumab is distributed primarily in the circulatory system.

Metabolism and Elimination- Specific metabolism studies were not conducted, because alirocumab is a protein.

Alirocumab is expected to degrade to small peptides and individual amino acids

. In clinical studies where 8 Reference ID: 3797282 alirocumab was administered in combination with atorvastatin or rosuvastatin, no relevant changes in statin concentrations were observed in the presence of repeated administration of alirocumab, indicating that cytochrome P450 enzymes (mainly CYP3A4 and CYP2C9) and transporter proteins such as P-gp and OATP were not affected by alirocumab

. Two elimination phases were observed for alirocumab. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of alirocumab is largely through a non-saturable proteolytic pathway.

Based on a population pharmacokinetic analysis, the median apparent half-life of alirocumab at steady state was 17 to 20 days in patients receiving alirocumab at subcutaneous doses of 75 mg Q2W or 150 mg Q2W.

Specific Populations- A population pharmacokinetic analysis was conducted on data from 2799 subjects. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence alirocumab pharmacokinetics.

No dose adjustments are recommended for these demographics. Pediatric PRALUENT has not been studied in pediatric patients 

Renal Impairment- Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of alirocumab. No data are available in patients with severe renal impairme

Hepatic Impairment- Following administration of a single 75 mg SC dose, alirocumab pharmacokinetic profiles in subjects with mild and moderate hepatic impairment were similar to those in subjects with normal hepatic function.

No data are available in patients with severe hepatic impairment.

Drug-Drug Interactions- The median apparent half-life of alirocumab is reduced to 12 days when administered with a statin; however, this difference is not clinically meaningful and does not impact dosing recommendations.

USE IN SPECIFIC POPULATIONS-

1. Pregnancy Risk Summary -

There are no available data on use of PRALUENT in pregnant women to inform a drug associated risk. In animal reproduction studies, there were no effects on embryo-fetal development when rats were subcutaneously administered alirocumab during organogenesis at dose exposures up to 12-fold the exposure at the maximum recommended human dose of 150 mg every two weeks.

FDA’s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester.

Consider the benefits and risks of PRALUENT and possible risks to the fetus before prescribing PRALUENT to pregnant women.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data

The lowest dose tested in the monkey resulted in humoral immune suppression; therefore it is unknown if this effect would be observed at clinical exposure.

2. Lactation Risk Summary There is no information regarding the presence of alirocumab in human milk, the effects on the breastfed infant, or the effects on milk production.

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for PRALUENT and any potential adverse effects on the breastfed infant from PRALUENT or from the underlying maternal condition. Human IgG is present in human milk, but published data suggest that breastmilk IgG antibodies do not enter the neonatal and infant circulation in substantial amounts.

3. Pediatric Use Safety and efficacy in pediatric patients have not been established.

4. Geriatric Use In controlled studies, 1158 patients treated with PRALUENT were =65 years of age and 241 patients treated with PRALUENT were =75 years of age.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

5. Renal Impairment No dose adjustment is needed for patients with mild or moderately impaired renal function. No data are available in patients with severe renal impairment. [See Clinical Pharmacology (12.3).]

6. Hepatic Impairment No dose adjustment is needed for patients with mild or moderate hepatic impairment. No data are available in patients with severe hepatic impairment.