FDA Label for Rezipres

1 Indications And Usage

REZIPRES^® is indicated for the treatment of clinically important hypotension occurring in the setting of anesthesia.

2 Dosage And Administration

2.1 General Dosage And Administration Instructions

REZIPRES^® 47 mg/mL must be diluted before administration as an intravenous bolus to achieve the desired concentration. Dilute with 0.9% Sodium Chloride Injection or 5% Dextrose Injection

REZIPRES^® 9.4 mg/mL can be either used as provided at 9.4 mg/mL or it can be diluted, with 5% Dextrose Injection or 0.9% Sodium Chloride Injection, to achieve the desired concentration, before administration as an intravenous bolus.

If the Rezipres diluted solution is not used immediately, store at controlled room temperature at 20°C to 25°C (68°F to 77°F) for up to 4 hours or refrigerate at 2°C to 8°C (36°F to 46°F) for no more than 24 hours. Discard the unused Rezipres diluted solution after 4 hours if stored at controlled room temperature or after 24 hours if refrigerated.

REZIPRES^® 4.7 mg/mL is a premixed formulation. Do not dilute prior to use.

• REZIPRES^® is a clear, colorless solution. Discard any unused portion.
• Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is not clear or if particulate matter is present.

2.2 Dosing For Treatment Of Clinically Important Hypotension In The Setting Of Anesthesia

The recommended dosages for the treatment of clinically important hypotension in the setting of anesthesia is an initial dose of 4.7 mg to 9.4 mg administered by intravenous bolus. Administer additional boluses as needed, not to exceed a total dosage of 47 mg.

• Adjust dosage according to the blood pressure goal (i.e., titrate to effect).

2.3 Prepare A 4.7 Mg/Ml Solution For Bolus Intravenous Administration

REZIPRES^® 47 mg/mL

• Withdraw 47 mg (1 mL of 47 mg/mL) of REZIPRES^® 47 mg/mL and dilute with 9 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
• Withdraw an appropriate dose of the 4.7 mg/mL solution prior to bolus intravenous administration.

REZIPRES^® 9.4 mg/mL

• Withdraw 5 mL of REZIPRES^® 9.4 mg/mL and dilute with 5 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection.
• Withdraw an appropriate dose of the 4.7 mg/mL solution prior to bolus intravenous administration.

2.4 Direct Administration Of 9.4 Mg/Ml Solution For Bolus Intravenous

REZIPRES^® if used as provided at 9.4 mg/ml:

• withdraw an appropriate dose of REZIPRES^® 9.4 mg/mL solution prior to bolus intravenous administration.

3 Dosage Forms And Strengths

REZIPRES^® 47 mg/mL
REZIPRES^® 47 mg/mL is a clear, colorless solution available in a one point cut clear colorless glass 2 mL single-dose ampule that contains 1 mL of solution, corresponding to 47 mg of ephedrine hydrochloride, equivalent to 38 mg of ephedrine base.

REZIPRES^® 47 mg/5 mL (9.4 mg/mL)
REZIPRES^® 47 mg/5mL is a clear, colorless solution available in a one point cut clear colorless glass single-dose ampule equivalent to 38 mg/5 mL ephedrine base (9.4 mg/mL ephedrine hydrochloride, equivalent to 7.7 mg/mL ephedrine base)

REZIPRES^® 23.5 mg/5 mL (4.7 mg/mL)
REZIPRES^® 23.5 mg/ 5mL is a clear, colorless solution, available in a one point cut clear colorless glass single-dose ampule, equivalent to 19 mg/5 mL of ephedrine base (4.7 mg/mL ephedrine hydrochloride, equivalent to 3.8 mg/mL of ephedrine base).

REZIPRES^® 47 mg/10 mL (4.7 mg/ mL)
REZIPRES^® 47 mg/10 mL is a clear, colorless solution, available in a clear colorless glass single-dose Vial, equivalent to 38 mg/10 mL of ephedrine base (4.7 mg/mL ephedrine hydrochloride, equivalent to 3.8 mg/mL of ephedrine base).

4 Contraindications

None

5 Warnings And Precautions

5.1 Pressor Effect With Concomitant Oxytocic Drugs

Serious postpartum hypertension has been described in patients who received both a vasopressor (i.e., methoxamine, phenylephrine, ephedrine) and an oxytocic (i.e., methylergonovine, ergonovine) [see Drug Interactions (7)]. Some of these patients experienced a stroke. Carefully monitor the blood pressure of individuals who have received both REZIPRES^® and an oxytocic.

5.2 Tolerance And Tachyphylaxis

Data indicate that repeated administration of ephedrine can result in tachyphylaxis. Clinicians treating anesthesia-induced hypotension with REZIPRES^® should be aware of the possibility of tachyphylaxis and should be prepared with an alternative pressor to mitigate unacceptable responsiveness.

5.3 Risk Of Hypertension When Used Prophylactically

When used to prevent hypotension, ephedrine has been associated with an increased incidence of hypertension compared with when ephedrine is used to treat hypotension.

6 Adverse Reactions

The following adverse reactions associated with the use of ephedrine were identified in the literature. 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.

Gastrointestinal disorders: Nausea, vomiting

Cardiac disorders: Tachycardia, palpitations (thumping heart), reactive hypertension, bradycardia, ventricular ectopics, R-R variability

Nervous system disorders: Dizziness

Psychiatric disorders: Restlessness

7 Drug Interactions

7.1 Interactions That Augment Pressor Effect

7.2 Interactions That Antagonize The Pressor Effect

7.3 Other Drug Interaction

8 Use In Specific Populations

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of ephedrine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection,and it may be useful to monitor renal function.

8.6 Renal Impairment

Ephedrine and its metabolite are excreted in urine. In patients with renal impairment, excretion of ephedrine is likely to be affected with a corresponding increase in elimination half-life, which will lead to slow elimination of ephedrine and consequently prolonged pharmacological effect and potentially adverse reactions. Monitor patients with renal impairment carefully after the initial bolus dose for adverse events.

10 Overdosage

Overdose of REZIPRES^® can cause a rapid rise in blood pressure. In the case of an overdose, careful monitoring of blood pressure is recommended. If blood pressure continues to rise to an unacceptable level, parenteral antihypertensive agents can be administered at the discretion of the clinician.

11 Description

REZIPRES^® is an alpha- and beta-adrenergic agonist and a norepinephrine-releasing agent. The chemical name of ephedrine hydrochloride is (1R,2S)-(-)-2-methylamino-1-phenyl-1-propanol hydrochloride, and the molecular weight is 201.7 g/mol. Its structural formula is depicted below:

rezipres-01 - chemical structure

Ephedrine hydrochloride is freely soluble in water, soluble in ethanol and stable in aqueous solution.

REZIPRES^® 47 mg/mL

REZIPRES^® 47 mg/mL is a clear, colorless, sterile solution for intravenous injection. It must be diluted before intravenous administration.

Each mL contains ephedrine hydrochloride 47 mg (equivalent to 38 mg ephedrine base) in water for injection. The pH is adjusted with sodium hydroxide and hydrochloric acid if necessary. The pH range is 5.0 to 6.5.

REZIPRES^® 47 mg/5 mL (9.4 mg/mL)

REZIPRES^® 9.4 mg/mL is a clear, colorless, sterile solution for intravenous injection. It can either be used as provided or diluted at 4.7 mg/mL, before intravenous administration.

Each mL contains ephedrine hydrochloride 9.4 mg (equivalent to 7.7 mg ephedrine base) and sodium chloride 6.0 mg in water for injection. The pH is adjusted with sodium hydroxide and hydrochloric acid if necessary. The pH range is 5.0 to 6.5.

REZIPRES^® 23.5 mg/5 mL (4.7 mg/mL)

REZIPRES^® 4.7 mg/mL is a clear, colorless, sterile solution for intravenous injection. It must not be diluted prior to use.

Each mL contains ephedrine hydrochloride 4.7 mg (equivalent to 3.8 mg ephedrine base) and sodium chloride 7.5 mg in water for injection. The pH is adjusted with sodium hydroxide and hydrochloric acid if necessary. The pH range is 5.0 to 6.5.

REZIPRES^® 47 mg/10 mL (4.7 mg/mL)

REZIPRES^® 4.7 mg/mL is a clear, colorless, sterile solution for intravenous injection. It must not be diluted prior to use.

Each mL contains ephedrine hydrochloride 4.7 mg (equivalent to 3.8 mg ephedrine base) and sodium chloride 7.5 mg in water for injection. The pH is adjusted with sodium hydroxide and hydrochloric acid if necessary. The pH range is 5.0 to 6.5

12 Clinical Pharmacology

12.1 Mechanism Of Action

Ephedrine is a sympathomimetic amine that directly acts as an agonist at α- and β-adrenergic receptors and indirectly causes the release of norepinephrine from sympathetic neurons. Pressor effects by direct alpha- and beta-adrenergic receptor activation are mediated by increases in arterial pressures, cardiac output, and peripheral resistance. Indirect adrenergic stimulation is caused by norepinephrine release from sympathetic nerves.

12.2 Pharmacodynamics

Ephedrine stimulates heart rate and cardiac output and variably increases peripheral resistance; as a result, ephedrine usually increases blood pressure. Stimulation of the α-adrenergic receptors of smooth muscle cells in the bladder base may increase the resistance to the outflow of urine. Activation of β- adrenergic receptors in the lungs promotes bronchodilation.

The overall cardiovascular effect from ephedrine is the result of a balance among α-1 adrenoceptor- mediated vasoconstriction, β-2 adrenoceptor-mediated vasoconstriction, and β-2 adrenoceptor-mediated vasodilatation. Stimulation of the β-1 adrenoceptors results in positive inotrope and chronotrope action.

Tachyphylaxis to the pressor effects of ephedrine may occur with repeated administration [see Warnings and Precautions 5.2].

12.3 Pharmacokinetics

Publications studying pharmacokinetics of oral administration of (-)-ephedrine support that (-)-ephedrine is metabolized into norephedrine. However, the metabolism pathway is unknown. Both the parent drug and the metabolite are excreted in urine. Limited data after IV administration of ephedrine support similar observations of urinary excretion of drug and metabolite. The plasma elimination half-life of ephedrine following oral administration was about 6 hours.

Ephedrine crosses the placental barrier [see Use in Specific Populations 8.1].

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

14 Clinical Studies

The evidence for the efficacy of REZIPRES^® is derived from the published literature. Increases in blood pressure following administration of ephedrine were observed in 14 studies, including 9 where ephedrine was used in pregnant women undergoing neuraxial anesthesia during Cesarean delivery, 1 study in non-obstetric surgery under neuraxial anesthesia, and 4 studies in patients undergoing surgery under general anesthesia. Ephedrine has been shown to raise systolic and mean blood pressure when administered as a bolus dose following the development of hypotension during anesthesia.

16 How Supplied/Storage And Handling

REZIPRES^® is a clear, colorless solution supplied as follows:

Store REZIPRES^® at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

For single-dose Ampules. If the Rezipres diluted solution is not used immediately, store at controlled room temperature at 20°C to 25°C (68°F to 77°F) for up to 4 hours or refrigerate at 2°C to 8°C (36°F to 46°F) for no more than 24 hours. Discard the unused Rezipres diluted solution after 4 hours if stored at controlled room temperature or after 24 hours if refrigerated.

For single dose Vials, discard any unused portion. Product is light sensitive. Store in carton until time of use.

17 Patient Counseling Information

If applicable, inform patient, family member, or caregiver that certain medical conditions and medications might influence how REZIPRES^® works.

Principal Display Panel-47Mg/10Ml Single Vial

NDC 43598-181-11

REZIPRES^®: Ephedrine Hydrochloride Injection
10mL single dose vial

Dr. Reddy's Laboratories Inc.

Carton label

rezipres-02 - carton

Vial label