Vazculep

VAZCULEP- phenylephrine hydrochloride injection
Avadel Legacy Pharmaceuticals, LLC

1 INDICATIONS AND USAGE

VAZCULEP is indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosage and Administration Instructions

VAZCULEP must be diluted before administration as an intravenous bolus or continuous intravenous infusion to achieve the desired concentration:

• Bolus: Dilute with normal saline or 5% dextrose in water.
• Continuous infusion: Dilute with normal saline or 5% dextrose in water.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if the solution is colored or cloudy, or if it contains particulate matter. The diluted solution should not be held for more than 4 hours at room temperature or for more than 24 hours under refrigerated conditions. Discard any unused portion.

During VAZCULEP administration:

• Correct intravascular volume depletion.
• Correct acidosis. Acidosis may reduce the effectiveness of phenylephrine.

2.2 Dosing for Treatment of Hypotension during Anesthesia

The following are the recommended dosages for the treatment of hypotension during anesthesia.

• The recommended initial dose is 40 to 100 mcg administered by intravenous bolus. Additional boluses may be administered every 1 to 2 minutes as needed; not to exceed a total dosage of 200 mcg.
• If blood pressure is below the target goal, start a continuous intravenous infusion with an infusion rate of 10 to 35 mcg/minute; not to exceed 200 mcg/minute.
• Adjust dosage according to the blood pressure goal.

2.3 Prepare a 100 mcg/mL Solution for Bolus Intravenous Administration

For bolus intravenous administration, prepare a solution containing a final concentration of 100 mcg/mL of VAZCULEP:

• Withdraw 10 mg (1 mL of 10 mg/mL) of VAZCULEP and dilute with 99 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP.
• Withdraw an appropriate dose from the 100 mcg/mL solution prior to bolus intravenous administration.

2.4 Prepare a Solution for Continuous Intravenous Administration

For continuous intravenous infusion, prepare a solution containing a final concentration of 20 mcg/mL of VAZCULEP in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP:

• Withdraw 10 mg (1 mL of 10 mg/mL) of VAZCULEP and dilute with 500 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP.

2.5 Directions for Dispensing from Pharmacy Bulk Vial

The Pharmacy Bulk Vial is intended for dispensing of single doses to multiple patients in a pharmacy admixture program and is restricted to the preparation of admixtures for infusion. Each closure shall be penetrated only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. The Pharmacy Bulk Vial is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). Dispensing from a pharmacy bulk vial should be completed within 4 hours after the vial is penetrated.

3 DOSAGE FORMS AND STRENGTHS

VAZCULEP (phenylephrine hydrochloride) Injection, 10 mg/mL, for intravenous use, is available in three vial sizes:

• Injection: 10 mg/mL as a clear, colorless solution in a single-dose 1 mL vial (10 mg of phenylephrine hydrochloride per vial)
• Injection: 10 mg/mL as a clear, colorless solution in Pharmacy Bulk Package 5 mL vial (50 mg of phenylephrine hydrochloride per vial) that will provide five 1 mL single doses
• Injection: 10 mg/mL as a clear, colorless solution in Pharmacy Bulk Package 10 mL vial (100 mg of phenylephrine hydrochloride per vial) that will provide ten 1 mL single doses

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension

Because of its increasing blood pressure effects, VAZCULEP can precipitate angina in patients with severe arteriosclerosis or history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure.

5.2 Peripheral and Visceral Ischemia

VAZCULEP can cause excessive peripheral and visceral vasoconstriction and ischemia to vital organs, particularly in patients with extensive peripheral vascular disease.

5.3 Skin and Subcutaneous Necrosis

Extravasation of VAZCULEP can cause necrosis or sloughing of tissue. The infusion site should be checked for free flow. Care should be taken to avoid extravasation of VAZCULEP.

5.4 Bradycardia

VAZCULEP can cause severe bradycardia and decreased cardiac output.

5.5 Allergic Reactions

VAZCULEP contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

5.6 Renal Toxicity

VAZCULEP can increase the need for renal replacement therapy in patients with septic shock. Monitor renal function.

5.7 Risk of Augmented Pressor Effect in Patients with Autonomic Dysfunction

The increasing blood pressure response to adrenergic drugs, including VAZCULEP, can be increased in patients with autonomic dysfunction, as may occur with spinal cord injuries.

5.8 Pressor Effect with Concomitant Oxytocic Drugs

Oxytocic drugs potentiate the increasing blood pressure effect of sympathomimetic pressor amines including VAZCULEP [see Drug Interactions (7.1)] , with the potential for hemorrhagic stroke.

6 ADVERSE REACTIONS

Adverse reactions to VAZCULEP are primarily attributable to excessive pharmacologic activity. Adverse reactions reported in published clinical studies, observational trials, and case reports of VAZCULEP are listed below by body system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Cardiac disorders: Reflex bradycardia, lowered cardiac output, ischemia, hypertension, arrhythmias

Gastrointestinal disorders: Epigastric pain, vomiting, nausea

Nervous system disorders: Headache, blurred vision, neck pain, tremors

Vascular disorders: Hypertensive crisis

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Skin and subcutaneous tissue disorders: Pruritis

7 DRUG INTERACTIONS

7.1 Interactions that Augment Pressor Effect

The increasing blood pressure effect of VAZCULEP is increased in patients receiving:

• Monoamine oxidase inhibitors (MAOI)
• Oxytocin and oxytocic drugs
• Tricyclic antidepressants
• Angiotensin, aldosterone
• Atropine
• Steroids, such as hydrocortisone
• Norepinephrine transporter inhibitors, such as atomoxetine
• Ergot alkaloids, such as methylergonovine maleate

7.2 Interactions that Antagonize the Pressor Effect

The increasing blood pressure effect of VAZCULEP is decreased in patients receiving:

• α-adrenergic antagonists
• Phosphodiesterase Type 5 inhibitors
• Mixed α- and β-receptor antagonists
• Calcium channel blockers, such as nifedipine
• Benzodiazepines
• ACE inhibitors
• Centrally acting sympatholytic agents, such as reserpine, guanfacine

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Data from randomized controlled trials and meta-analyses with phenylephrine hydrochloride injection use in pregnant women during Cesarean section have not established a drug-associated risk of major birth defects and miscarriage. These studies have not identified an adverse effect on maternal outcomes or infant Apgar scores [see Data]. There are no data on the use of phenylephrine during the first or second trimester. In animal reproduction and development studies in normotensive animals, evidence of fetal malformations was noted when phenylephrine was administered during organogenesis via a 1-hour infusion at 1.2 times the human daily dose (HDD) of 10 mg/60 kg/day. Decreased pup weights were noted in offspring of pregnant rats treated with 2.9 times the HDD [See Data]. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Clinical Considerations

Disease-Associated Maternal and/or Embryofetal Risk

Untreated hypotension associated with spinal anesthesia for Cesarean section is associated with an increase in maternal nausea and vomiting. A sustained decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis.

Data

Human Data

Published randomized controlled trials over several decades, which compared the use of phenylephrine injection to other similar agents in pregnant women during Cesarean section, have not identified adverse maternal or infant outcomes. At recommended doses, phenylephrine does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree.

There are no studies on the safety of phenylephrine injection exposure during the period of organogenesis, and therefore, it is not possible to draw any conclusions on the risk of birth defects following exposure to phenylephrine injection during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to phenylephrine injection.

Animal Data

No clear malformations or fetal toxicity were reported when normotensive pregnant rabbits were treated with phenylephrine via continuous intravenous infusion over 1 hour (0.5 mg/kg/day; approximately equivalent to a HDD based on body surface area) from Gestation Day 7 to 19. At this dose, which demonstrated no maternal toxicity, there was evidence of developmental delay (altered ossification of sternebra).

In a non-GLP dose range-finding study in normotensive pregnant rabbits, fetal lethality and cranial, paw, and limb malformations were noted following treatment with 1.2 mg/kg/day of phenylephrine via continuous intravenous infusion over 1 hour (2.3-times the HDD). This dose was clearly maternally toxic (increased mortality and significant body weight loss). An increase in the incidence of limb malformation (hyperextension of the forepaw) coincident with high fetal mortality was noted in a single litter at 0.6 mg/kg/day (1.2-times the HDD) in the absence of maternal toxicity.

No malformations or embryo-fetal toxicity were reported when normotensive pregnant rats were treated with up to 3 mg/kg/day phenylephrine via continuous intravenous infusion over 1 hour (2.9-times the HDD) from Gestation Day 6 to 17. This dose was associated with some maternal toxicity (decreased food consumption and body weights).

Decreased pup weights were reported in a pre- and postnatal development toxicity study in which normotensive pregnant rats were administered phenylephrine via continuous intravenous infusion over 1 hour (0.3, 1.0, or 3.0 mg/kg/day; 0.29, 1, or 2.9 times the HDD) from Gestation Day 6 through Lactation Day 21). No adverse effects on growth and development (learning and memory, sexual development, and fertility) were noted in the offspring of pregnant rats at any dose tested. Maternal toxicities (mortality late in gestation and during lactation period, decreased food consumption and body weight) occurred at 1 and 3 mg/kg/day of phenylephrine (equivalent to and 2.9 times the HDD, respectively).