USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Pregnancy: Use amiodarone during pregnancy only if the potential benefit to the mother justifies the risk to the fetus (8.1).

• Nursing mothers: Advise mothers to discontinue breast feeding (8.3).
• Pediatric use: Safety and efficacy have not been established (8.4).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.8)].

Teratogenic Effects

Amiodarone and desethylamiodarone cross the placenta.

Reported risks include:

• neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles
• neonatal hypothyroidism(with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure
• neonatal hyperthyroxinemia
• neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia.
• jerk nystagmus with synchronous head titubation
• fetal growth retardation
• premature birth

Amiodarone has caused a variety of adverse effects in animals.

Amiodarone was given intravenously to rabbits at dosages of 5, 10, or 25 mg/kg per day (about 0.1, 0.3, and 0.7 times the human intravenous maintenance dose of 0.5 mg/min on a body surface area basis), during gestation days 8 to 16 (organogenesis). The incidence of maternal deaths increased with increasing dose and occurred in all treated groups, and controls. Mean fetal weights were significantly decreased in the low and middle dose groups and embryotoxicity (as manifested by fewer full- term fetuses and increased resorptions) occurred at dosages of 10 mg/kg and above. There were no significant differences in the number of minor fetal abnormalities and no major fetal abnormalities were observed.

Amiodarone was administered by continuous intravenous infusion to rats at dosages of 25, 50, or 100 mg/kg per day (about 0.3, 0.7, and 1.3 times the human intravenous maintenance dose of 0.5 mg/min on a body surface area basis) during gestation days 8 to 16 (organogenesis). Maternal toxicity (manifest as reduced weight gain and food consumption) and embryotoxicity (manifest as increased resorptions, decreased live litter size and fetal body weights, and delayed sternal and metacarpal ossification) were observed in the 100 mg/kg group. The delayed ossification was reversible and related to decreased fetal weight. Fetal thyroid tissues appeared normal in all groups.

Nonteratogenic Effects

Very high concentrations of amiodarone and desethylamiodarone may be found in testes. Elevated follicle-stimulating hormone and luteinizing hormone levels, suggestive of testicular dysfunction, have been reported in men on long- termamiodarone treatment.

While planning pregnancy after discontinuation of amiodarone treatment, consider the long half-life of amiodarone and its metabolite DEA.

8.2 Labor and Delivery

It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. Preclinical studies in rodents have not shown any effect on the duration of gestation or on parturition.

8.3 Nursing Mothers

Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered amiodarone have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone must be weighed against the potential benefit of arrhythmia suppression in the mother. Advise the mother to discontinue nursing.

8.4 Pediatric Use

The safety and effectiveness of amiodarone in pediatric patients have not been established; therefore, the use of amiodarone in pediatric patients is not recommended. In a pediatric trial of 61 patients, aged 30 days to 15 years, hypotension (36%), bradycardia (20%), and AV block (15%) were common dose- related adverse reactions and were severe or life-threatening in some cases. Injection site reactions were seen in 5 (25%) of the 20 patients receiving intravenous amiodarone through a peripheral vein irrespective of dose regimen.

Amiodarone hydrochloride injection contains the preservative benzyl alcohol [see Description (11)] . There have been reports of fatal “gasping syndrome” in neonates (children less than one month of age) following the administration of intravenous solutions containing the preservative benzyl alcohol. Symptoms include a striking onset of gasping respiration, hypotension, bradycardia, and cardiovascular collapse.

8.5 Geriatric Use

Clinical studies of amiodarone 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. Carefully consider dose selection in an elderly patient. In general, start at the low end of the dosing range in the elderly to reflect the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

---

NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies were conducted with intravenous administration of amiodarone. However, oral amiodarone caused a statistically significant, dose- related increase in the incidence of thyroid tumors (follicular adenoma and carcinoma) in rats. The incidence of thyroid tumors in rats was greater than the incidence in controls even at the lowest dose level tested, i.e., 5 mg/kg/day (much less, on a body surface area basis, than the maximum recommended human maintenance dose of 600 mg/day).

Mutagenicity studies conducted with amiodarone hydrochloride (Ames, micronucleus, and lysogenic induction tests) were negative.

No fertility studies were conducted with intravenous administration of amiodarone. However, in a study in which amiodarone hydrochloride was orally administered to male and female rats, beginning 9 weeks prior to mating, reduced fertility was observed at a dose level of 90 mg/kg/day (approximately 1.4 times the maximum recommended human maintenance dose of 600 mg/day).

---

HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Amiodarone Hydrochloride Injection, USP is a sterile clear, pale yellow solution visually free from particulates available in glass vials packaged as follows:

---

** 150 mg per 3 mL (50 mg/mL):**

3 mL in 3 mL Single Dose Vials,
packaged in cartons of 10 NDC 55150-180-03****

---

** 450 mg per 9 mL (50 mg/mL):******

---

9 mL in 10 mL Single Dose Vials,
packaged in cartons of 10 NDC 55150-181-09

---

** 900 mg per 18 mL (50 mg/mL):**

18 mL in 20 mL Multiple Dose Vials,
packaged in cartons of 1 NDC 55150-182-18

---

** Store at** 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light and excessive heat.

Use carton to protect contents from light until used.

The vial stopper is not made with natural rubber latex.

---