Included as part of the PRECAUTIONS section.
Exacerbation Of Angina, Heart Failure, Or Pulmonary
Because of its increasing blood pressure effects,
BIORPHEN can precipitate angina in patients with severe arteriosclerosis or
history of angina, exacerbate underlying heart failure, and increase pulmonary
Peripheral And Visceral Ischemia
BIORPHEN can cause excessive peripheral and visceral
vasoconstriction and ischemia to vital organs, particularly in patients with
extensive peripheral vascular disease.
Skin And Subcutaneous Necrosis
Extravasation of BIORPHEN can cause necrosis or sloughing
of tissue. Avoid extravasation by checking infusion site for free flow.
BIORPHEN can cause severe bradycardia and decreased
BIORPHEN can increase the need for renal replacement
therapy in patients with septic shock. Monitor renal function.
Risk Of Augmented Pressor Affect In Patients With Autonomic
The increasing blood pressure response to adrenergic
drugs, including BIORPHEN, can be increased in patients with autonomic
dysfunction, as may occur with spinal cord injuries.
Pressor Effect With Concomitant Oxytocic Drugs
Oxytocic drugs potentiate the increasing blood pressure
effect of sympathomimetic pressor amines including BIORPHEN [see DRUG
INTERACTIONS], with the potential for hemorrhagic stroke.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies that evaluated the carcinogenic
potential of orally administered phenylephrine hydrochloride in F344/N rats and
B6C3F1 mice were completed 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 rats administered
approximately 50 mg/kg/day (48 times the HDD).
Phenylephrine hydrochloride tested negative in the in
vitro bacterial reverse mutation assay (S. typhimurium strains TA98,
TA100, TA1535 and TA1537), the in vitro chromosomal aberrations assay, the in
vitro 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 did not impair mating, fertility, or
reproductive outcome in normotensive male rats treated with 3 mg/kg/day
phenylephrine 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 and female rats treated with the same dosing regimen for 14 days
prior to mating and through Gestation Day 6. This dose was associated with
increased mortality in both male and female rats and decreased body weight gain
in treated males. There were decreased caudal sperm density and increased
abnormal sperm reported in males treated with 3 mg/kg/day phenylephrine (2.9
times the HDD).
Use In Specific Populations
Data from randomized controlled trials and meta-analyses
with phenylephrine hydrochloride injection use in pregnant women during
caesarean 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 is 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%,
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.
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 variability to a significant
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
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).
There are no data on the presence of Phenylephrine
Hydrochloride Injection or its metabolite in human or animal milk, the effects
on the breastfed infant, or the effects on milk production. The developmental
and health benefits of breastfeeding should be considered along with the
motherÃ¢â¬™s clinical need for phenylephrine hydrochloride injection and any
potential adverse effects on the breastfed infant from phenylephrine
hydrochloride injection or from the underlying maternal condition.
Safety and effectiveness in pediatric patients have not
Clinical studies of phenylephrine 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.
In patients with liver cirrhosis [Child Pugh Class B and
Class C], dose-response data indicate decreased responsiveness to
phenylephrine. Start dosing in the recommended dose range but more
phenylephrine may be needed in this population.
In patients with end stage renal disease (ESRD),
dose-response data indicate increased responsiveness to phenylephrine. Consider
starting at the lower end of the recommended dose range, and adjusting dose
based on the target blood pressure goal.