Phenylephrine hydrochloride

Uses and Indications

Phenylephrine Hydrochloride is indicated for the treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia. This drug is also indicated for increasing blood pressure in adults with hypotension occurring in settings such as septic shock and anesthesia.

In addition, Phenylephrine Hydrochloride Ophthalmic Solution is indicated to dilate the pupil and is classified as an alpha-1 adrenergic receptor agonist.

Limitations of Use

There are no teratogenic or nonteratogenic effects mentioned in the provided data.

Dosage and Administration

Phenylephrine hydrochloride is administered intravenously either as a bolus or as a continuous infusion. The formulation at 10 mg/mL must be diluted before administration.

For the treatment of hypotension during anesthesia, the following dosing guidelines apply:

Bolus Intravenous Injection: The initial dose ranges from 40 mcg to 100 mcg, administered every 1 to 2 minutes as needed, not to exceed a total of 200 mcg.

Intravenous Continuous Infusion: The infusion rate should be titrated to effect, starting at 10 mcg/min and not exceeding 35 mcg/min.

For perioperative hypotension, an alternative dosing regimen is available:

Bolus Intravenous Administration: Doses can range from 50 mcg to 250 mcg.

Intravenous Continuous Infusion for Perioperative Hypotension: The infusion rate should be between 0.5 mcg/kg/minute to 1.4 mcg/kg/minute, titrated to effect.

For patients experiencing vasodilatory shock, the continuous infusion rate should be adjusted between 0.5 mcg/kg/minute to 6 mcg/kg/minute, also titrated to effect.

For ophthalmic use, patients aged 1 year and older should receive one drop of Phenylephrine Hydrochloride Ophthalmic Solution (2.5% or 10% strength) applied to the conjunctival fornix at intervals of 3 to 5 minutes, up to a maximum of 3 drops per eye. For pediatric patients under 1 year of age, one drop of 2.5% strength should be instilled at the same intervals and maximum.

It is essential to adjust the dose according to the pressor response, ensuring that the administration is tailored to the individual patient's needs.

Contraindications

Patients with hypersensitivity to phenylephrine hydrochloride or any of its components should not use this medication. Additionally, the 10% strength of phenylephrine hydrochloride is contraindicated in patients with hypertension or thyrotoxicosis, as well as in pediatric patients less than 1 year of age due to the increased risk of systemic toxicity.

Warnings and Precautions

Severe Cardiovascular Reactions Phenylephrine hydrochloride can precipitate angina in patients with severe arteriosclerosis or a history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure. It may also cause severe bradycardia and decreased cardiac output.

Peripheral and Visceral Ischemia The use of phenylephrine hydrochloride can lead to excessive peripheral and visceral vasoconstriction, resulting in ischemia to vital organs.

Extravasation Risks Extravasation during intravenous administration may cause necrosis or sloughing of tissue. Care should be taken to avoid this complication.

Concomitant Use with Oxytocic Drugs The pressor effect of sympathomimetic pressor amines is potentiated when phenylephrine hydrochloride is used in conjunction with oxytocic drugs.

Allergic Reactions Allergic-type reactions, including those related to sulfite, have been reported with phenylephrine hydrochloride injection (10 mg/mL).

Monitoring Requirements

• Blood pressure should be monitored in patients with cardiovascular disease, particularly when using the 10% strength of phenylephrine hydrochloride.

• Caution is advised in pediatric patients under 5 years of age and in patients with cardiovascular disease or hyperthyroidism. In high-risk patients, blood pressure should be monitored post-treatment.

Topical Ophthalmic Use Phenylephrine hydrochloride is indicated for topical ophthalmic use only and is not for injection. Serious cardiovascular reactions, including fatal ventricular arrhythmias, have been reported with the 10% solution.

Rebound Effects Rebound miosis has been reported one day after instillation of the ophthalmic solution.

Side Effects

Most common adverse reactions reported in patients receiving Phenylephrine Hydrochloride include:

• Nausea

• Vomiting

• Headache

• Nervousness

Serious adverse reactions associated with Phenylephrine Hydrochloride include:

• Severe bradycardia and decreased cardiac output: This can occur in susceptible individuals, particularly those with pre-existing cardiovascular conditions.

• Exacerbation of angina, heart failure, or pulmonary arterial hypertension: Phenylephrine can precipitate angina in patients with severe arteriosclerosis or a history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure.

• Peripheral and visceral ischemia: Excessive peripheral and visceral vasoconstriction may lead to ischemia of vital organs.

• Skin and subcutaneous necrosis: Extravasation during intravenous administration may cause necrosis or sloughing of tissue.

• Allergic-type reactions: Hypersensitivity reactions, including sulfite allergy, have been reported.

Overdose symptoms may include:

• Rapid rise in blood pressure

• Headache

• Vomiting

• Hypertension

• Reflex bradycardia

• Sensation of fullness in the head

• Tingling of the extremities

• Cardiac arrhythmias, including ventricular extrasystoles and ventricular tachycardia

Ocular adverse reactions associated with the use of Phenylephrine Hydrochloride in solution or drops include:

• Eye pain and stinging upon instillation

• Temporary blurred vision

• Photophobia

Cardiovascular adverse reactions may also include:

• Syncope

• Myocardial infarction

• Tachycardia

• Arrhythmia

• Subarachnoid hemorrhage

Significant elevations in blood pressure have been noted, particularly in pediatric patients under 5 years of age and in patients with cardiovascular disease or hyperthyroidism. Monitoring of blood pressure is recommended in high-risk patients post-treatment.

Rebound miosis has been reported one day after instillation of the ocular formulation.

In clinical studies, the most common maternal adverse reactions associated with the use of Phenylephrine during neuraxial anesthesia include nausea and vomiting, which are often linked to hypotension, bradycardia, reactive hypertension, and transient arrhythmias.

Drug Interactions

Agonistic and antagonistic interactions involving Phenylephrine Hydrochloride are significant and can impact its clinical efficacy and safety profile.

Agonistic Interactions

Phenylephrine Hydrochloride may exhibit increased blood pressure effects when administered concurrently with the following agents:

• Monoamine Oxidase Inhibitors (MAOIs): These can enhance the pressor response.

• Oxytocin and Oxytocic Drugs: These may also potentiate the effects of Phenylephrine.

• Tricyclic Antidepressants: These drugs can increase the blood pressure response to Phenylephrine.

• Angiotensin and Aldosterone: These hormones may contribute to enhanced blood pressure effects.

• Atropine: This anticholinergic agent can augment the adrenergic response.

• Steroids: Corticosteroids may enhance the pressor effects of Phenylephrine.

• Norepinephrine Transport Inhibitors: These can increase the availability of norepinephrine, thus enhancing Phenylephrine's effects.

• Ergot Alkaloids: These compounds may also increase the blood pressure response.

Antagonistic Interactions

Conversely, the blood pressure effects of Phenylephrine may be diminished when used in conjunction with:

• α-Adrenergic Antagonists: These agents can block the effects of Phenylephrine.

• Phosphodiesterase Type 5 Inhibitors: These may reduce the efficacy of Phenylephrine.

• Mixed α- and β-Receptor Antagonists: These can interfere with the action of Phenylephrine.

• Calcium Channel Blockers: These agents may lower blood pressure and counteract Phenylephrine's effects.

• Benzodiazepines: These can have a sedative effect that may reduce the efficacy of Phenylephrine.

• ACE Inhibitors: These may also antagonize the effects of Phenylephrine.

• Centrally Acting Sympatholytic Agents: These can reduce sympathetic outflow, thereby diminishing Phenylephrine's effects.

Special Considerations

• Atropine-like Drugs: The use of atropine-like drugs may exaggerate the adrenergic pressor response when combined with Phenylephrine.

• Potent Inhalation Anesthetic Agents: These agents may potentiate cardiovascular depressant effects when used with Phenylephrine, necessitating careful monitoring.

Clinicians should be aware of these interactions to optimize therapeutic outcomes and minimize adverse effects when prescribing Phenylephrine Hydrochloride.

Pediatric Use

Safety and effectiveness of phenylephrine hydrochloride have not been established in pediatric patients across all formulations, including injection and solution forms.

Phenylephrine hydrochloride ophthalmic solution 10% is contraindicated in pediatric patients less than 1 year of age due to the increased risk of systemic toxicity. For patients 1 year of age or greater, one drop of phenylephrine hydrochloride ophthalmic solution 2.5% or 10% may be applied every 3 to 5 minutes to the conjunctival fornix as required, up to a maximum of 3 drops per eye per day. In pediatric patients less than 1 year of age, one drop of phenylephrine hydrochloride ophthalmic solution 2.5% should be instilled at 3 to 5 minute intervals, also up to a maximum of 3 drops per eye.

Caution should be exercised when using phenylephrine hydrochloride ophthalmic solution 10% in pediatric patients less than 5 years of age, as well as in those with hyperthyroidism or cardiovascular disease. Additionally, it is not known whether this drug is excreted in human milk.

Geriatric Use

Clinical studies of phenylephrine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly and younger patients.

In general, dose selection for elderly patients should be approached with caution. It is recommended to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies.

No overall differences in safety and effectiveness have been observed between elderly and younger adult patients. Nonetheless, careful monitoring is advised when administering phenylephrine to geriatric patients.

Pregnancy

In animal reproductive and developmental studies, phenylephrine hydrochloride has demonstrated some potential risks when administered during pregnancy. Decreased fetal body weights were observed at doses as low as 0.4 times the human daily dose (HDD) of 10 mg, with no malformations reported. However, an increased incidence of agenesis of the intermediate lobe of the lung, a visceral variation, was noted at levels as low as 0.08 times the HDD.

The estimated background risk of major birth defects and miscarriage for the general population is unknown; however, in clinically recognized pregnancies in the U.S., the estimated background risk of major birth defects is 2 to 4%, and the risk of miscarriage is 15 to 20%.

Data from randomized controlled trials and meta-analyses involving the use of phenylephrine hydrochloride injection in pregnant women during cesarean sections have not established a drug-associated risk of major birth defects or miscarriage. These studies have not identified adverse effects on maternal outcomes or infant Apgar scores. There are no data available regarding the use of phenylephrine during the first or second trimester.

In animal studies, evidence of fetal malformations was noted when phenylephrine was administered during organogenesis via a 1-hour infusion at 1.2 times the HDD. Additionally, decreased pup weights were reported in offspring of pregnant rats treated with 2.9 times the HDD. At recommended doses, phenylephrine does not appear to significantly affect fetal heart rate or fetal heart rate variability.

Untreated hypotension associated with spinal anesthesia for cesarean sections may lead to increased maternal nausea and vomiting, and a sustained decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis.

There are no studies on the safety of phenylephrine injection exposure during the period of organogenesis, making it impossible to draw conclusions regarding the risk of birth defects following exposure during pregnancy. Furthermore, there are no data on the risk of miscarriage following fetal exposure to phenylephrine injection.

No clear malformations or fetal toxicity were reported when normotensive pregnant rabbits were treated with phenylephrine via continuous intravenous infusion at doses equivalent to the HDD. However, at higher doses, maternal toxicity was observed, including increased mortality and significant body weight loss.

Phenylephrine hydrochloride should be administered to pregnant patients only if clearly needed, and careful consideration should be given to the potential risks versus benefits.

Lactation

There are no data available regarding the presence of phenylephrine hydrochloride or its metabolites in human or animal breast milk, nor are there any studies assessing its effects on breastfed infants or milk production. The developmental and health benefits of breastfeeding should be weighed against the clinical need for phenylephrine hydrochloride in lactating mothers, as well as any potential adverse effects on the breastfed infant stemming from the drug or the underlying maternal condition.

In animal studies, no adverse effects on offspring were observed when pregnant rats received phenylephrine hydrochloride at doses up to 200 mcg/day from Gestation Day 6 to Lactation Day 20. However, decreased pup weights were noted in a separate study involving higher doses (0.3, 1.0, or 3.0 mg/kg/day) administered via continuous intravenous infusion from Gestation Day 6 through Lactation Day 21. Maternal toxicities, including mortality late in gestation and during the lactation period, were reported at the higher doses.

Caution is advised when administering phenylephrine hydrochloride ophthalmic solutions (2.5% and 10%) to nursing women, as many drugs can be excreted in human milk. The potential risks to the breastfed infant should be carefully considered in the context of the mother's health needs.

Renal Impairment

In patients with end-stage renal disease (ESRD), particularly those undergoing hemodialysis, there is evidence suggesting increased responsiveness to phenylephrine. It is recommended that clinicians consider initiating treatment at the lower end of the recommended dose range for these patients. Dosing adjustments should be made based on the target blood pressure goal to ensure effective management while minimizing potential adverse effects.

For all other forms of phenylephrine hydrochloride, there is no specific information available regarding dosage adjustments, monitoring, or safety considerations for patients with renal impairment. Therefore, healthcare providers should exercise caution and consider individual patient factors when prescribing phenylephrine to those with reduced kidney function.

Hepatic Impairment

In patients with hepatic impairment, particularly those with liver cirrhosis classified as Child Pugh Class B and Class C, dose-response data indicate a decreased responsiveness to phenylephrine. It is recommended to start dosing within the standard recommended dose range; however, larger doses may be necessary to achieve the desired therapeutic effect in this population.

No specific information regarding dosage adjustments, special monitoring, or additional precautions for patients with liver problems is provided for phenylephrine hydrochloride in its various formulations, including injection and solution forms. Therefore, clinicians should exercise caution and consider individual patient factors when administering phenylephrine to patients with hepatic impairment.

Overdosage

Overdose of phenylephrine hydrochloride, particularly in the form of injection at a concentration of 10 mg/mL, can lead to a rapid rise in blood pressure. Symptoms associated with an overdose may include headache, vomiting, hypertension, reflex bradycardia, and cardiac arrhythmias such as ventricular extrasystoles and ventricular tachycardia. Additionally, patients may experience a sensation of fullness in the head and tingling of the extremities.

Management of phenylephrine overdose should include the prompt administration of a rapidly acting alpha-adrenergic blocking agent, such as phentolamine, to mitigate the hypertensive effects. Continuous monitoring of cardiovascular status is recommended to assess for any arrhythmias or significant changes in blood pressure. If symptoms such as anxiety or nausea are present, supportive care should be provided as necessary.

Nonclinical Toxicology

Carcinogenesis

Long-term animal studies evaluating the carcinogenic potential of orally administered phenylephrine hydrochloride in F344/N rats and B6C3F1 mice were conducted by the National Toxicology Program using the dietary route of administration. There was no evidence of carcinogenicity in mice administered approximately 270 mg/kg/day (131 times the human daily dose (HDD) of 10 mg/60 kg/day based on body surface area) or in rats administered approximately 50 mg/kg/day (48 times the HDD based on body surface area comparisons).

Mutagenesis

Phenylephrine hydrochloride tested negative in several in vitro assays, including the bacterial reverse mutation assay (S. typhimurium strains TA98, TA100, TA1535, and TA1537), the chromosomal aberrations assay, the sister chromatid exchange assay, and the in vivo rat micronucleus assay. Positive results were reported in only one of two replicates of the in vitro mouse lymphoma assay.

Impairment of Fertility

Phenylephrine hydrochloride did not impair mating, fertility, or reproductive outcomes in normotensive male rats treated with 3 mg/kg/day via continuous intravenous infusion over 1 hour (2.9 times the HDD) for 28 days prior to mating and for a minimum of 63 days prior to sacrifice. Female rats were treated with the same dosing regimen for 14 days prior to mating and through Gestation Day 6. This dosing was associated with increased mortality in both male and female rats and decreased body weight gain in treated males. Additionally, decreased caudal sperm density and increased abnormal sperm were reported in males treated with 3 mg/kg/day phenylephrine (2.9 times the HDD). No adverse effects on fertility or early embryonic development were noted when phenylephrine hydrochloride was administered at doses of 50 mcg, 100 mcg, or 200 mcg/kg/day (up to 0.2 times HDD) via single daily bolus injection for 28 days prior to mating to male rats or for 14 days prior to mating through Gestation Day 7 to female rats.

Storage and Handling

Phenylephrine Hydrochloride is supplied in various forms, including injection and solution/drops. The product is available in 1 mL vials for single use, as well as 5 mL and 10 mL vials designated as pharmacy bulk packages.

The storage conditions for Phenylephrine Hydrochloride are as follows:

• Store at 20°C to 25°C (68°F to 77°F), with excursions permitted between 15°C to 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature.

• Protect from light and excessive heat.

• Keep covered in the carton until time of use.

• The container should be kept tightly closed.

For handling the diluted solution:

• The diluted solution should not be held for more than 4 hours at room temperature or for more than 24 hours under refrigerated conditions (2°C to 8°C).

• Discard any unused portion after use.

For the ophthalmic solution/drops:

• After opening, the product can be used until the expiration date on the bottle.

• Do not use if the solution is brown or contains a precipitate.