Fentanyl Citrate (Page 5 of 7)


8.1 Pregnancy

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with Fentanyl Citrate Injection in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. No evidence of malformations was noted in animal studies completed to date [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% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Fentanyl Citrate Injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Fentanyl Citrate Injection, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.


Animal Data

Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.05 times the human dose of 100 mcg/kg on a mg/m2 basis) and 160 mcg/kg subcutaneously (0.26 times the human dose of 100 mcg/kg on a mg/m2 basis). There was no evidence of teratogenicity reported.

No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 0.81 times the human dose of 100 mcg/kg on a mg/m2 basis.

8.2 Lactation

Risk Summary

Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.38%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fentanyl Citrate Injection and any potential adverse effects on the breastfed infant from Fentanyl Citrate Injection or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to fentanyl through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential


Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and efficacy of Fentanyl Citrate Injection in children under two years of age have not been established.

Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery which included the combined use of fentanyl, pancuronium, and atropine. A direct cause and effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established.

8.5 Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to fentanyl. In general, use caution when selecting a dosage for an elderly patient, 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.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Fentanyl Citrate Injection slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2)].

Fentanyl 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 Hepatic Impairment

Fentanyl Citrate Injection should be administered with caution to patients with liver dysfunction because of the extensive hepatic metabolism. Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.

8.7 Renal Impairment

Fentanyl Citrate Injection should be administered with caution to patients with kidney dysfunction because of the renal excretion of fentanyl citrate and its metabolites. Reduce the dosage as needed and monitor for signs of respiratory depression, sedation, and hypotension.


9.1 Controlled Substance

Fentanyl Citrate Injection contains fentanyl, a Schedule II controlled substance.

9.2 Abuse

Fentanyl Citrate Injection contains fentanyl, a substance with high ‎potential for misuse and abuse, which ‎can lead to the development of ‎substance use disorder, including addiction [see Warnings and ‎‎Precautions (5.1)].

‎Misuse is the intentional use, for therapeutic purposes, of a drug by an ‎individual in a way other than ‎prescribed by a healthcare provider or for ‎whom it was not prescribed.‎

Abuse is the intentional, non-therapeutic use of a drug, even once, for its ‎desirable psychological or ‎physiological effects.‎

Drug addiction is a cluster of behavioral, cognitive, and physiological ‎phenomena that may include a ‎strong desire to take the drug, difficulties ‎in controlling drug use (e.g., continuing drug use despite ‎harmful ‎consequences, giving a higher priority to drug use than other activities and ‎obligations), and ‎possible tolerance or physical dependence.‎

Misuse and abuse of Fentanyl Citrate Injection increases risk of ‎overdose, which may lead to central ‎nervous system and respiratory ‎depression, hypotension, seizures, and death. The risk is increased with ‎‎concurrent abuse of Fentanyl Citrate Injection with alcohol and other ‎CNS ‎depressants. Abuse of and addiction to opioids in ‎some individuals may not be accompanied by ‎concurrent tolerance and ‎symptoms of physical dependence. In addition, abuse of opioids can ‎occur in ‎the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation ‎for signs of misuse, abuse, ‎and addiction, because use of opioid analgesic ‎products carries the risk of addiction even under ‎appropriate medical use. ‎Patients at high risk of Fentanyl Citrate Injection abuse include those with ‎a ‎history of prolonged use of any opioid, including products containing fentanyl, those with a ‎history of drug or alcohol abuse, or ‎those who use Fentanyl Citrate ‎Injection in combination with other abused drugs.‎‎

“Drug-seeking” behavior is very common in persons with substance use ‎disorders. Drug-seeking tactics ‎include emergency calls or visits near the ‎end of office hours, refusal to undergo appropriate ‎examination, testing, or ‎referral, repeated “loss” of prescriptions, tampering with prescriptions, ‎and ‎reluctance to provide prior medical records or contact information for ‎other treating healthcare ‎provider(s). “Doctor shopping” (visiting multiple ‎prescribers to obtain additional prescriptions) is ‎common among people ‎who abuse drugs and people with substance use disorder. Preoccupation ‎with ‎achieving adequate pain relief can be appropriate behavior in a ‎patient with inadequate pain control.‎

Fentanyl Citrate Injection, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic ‎reevaluation of therapy, and ‎proper dispensing and storage are ‎appropriate measures that help to limit abuse of opioid drugs.‎

Risks Specific to Abuse of Fentanyl Citrate Injection

Abuse of Fentanyl Citrate Injection poses a risk of overdose and death. The risk is increased with concurrent use of Fentanyl Citrate Injection with alcohol and/or other CNS depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

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