Fulvestrant

Fulvestrant therapy is said to be associated with serum enzyme elevations in up to 15% of patients, but the elevations are generally asymptomatic, transient and mild, rarely requiring dose adjustment or discontinuation. ALT elevations above 5 times the upper limit of normal occurred in only 1% to 2% of patients. However, specifics on the timing and course of serum enzyme elevations during fulvestrant therapy have not been described. In addition, no cases of clinically apparent liver injury with jaundice were reported in the prelicensure controlled trials of fulvestrant and none have been published since its approval in the United States and more wide-scale use. Nevertheless, the product label for fulvestrant mentions that "hepatitis and liver failure have been reported infrequently (

Fulvestrant is well-tolerated in most cases, according to multiple clinical trials. The most commonly encountered adverse effects were pain at the injection site and hot flashes. Other common side effects include headache, nausea, vomiting, loss of appetite, constipation, diarrhea, fatigue, abnormal liver function tests, urinary tract infections, and rashes. In one case study, toxic epidermal necrolysis was observed in a woman with ductal carcinoma of the breast five days after the initiation of fulvestrant.

An overdose of fulvestrant is not overly likely as its administration must be by healthcare practitioners in a controlled environment. Thus the toxicity that results from the overdose of fulvestrant has not been reported in studies. However, more research is necessary regarding the development of a protocol in case such an event occurs.

Fulvestrant competitively and reversibly binds to estrogen receptors present in cancer cells and achieves its anti-estrogen effects through two separate mechanisms. First, fulvestrant binds to the receptors and downregulates them so that estrogen is no longer able to bind to these receptors. Second, fulvestrant degrades the estrogen receptors to which it is bound. Both of these mechanisms inhibit the growth of tamoxifen-resistant as well as estrogen-sensitive human breast cancer cell lines.

/AQUATIC SPECIES/ ... In the present study, the effects and mechanism of action of ICI 182,780 (ICI) were investigated in the teleost fish, sea bream (Sparus auratus). Three independent in vivo experiments were performed in which mature male tilapia (Oreochromis mossambicus) or sea bream received intra-peritoneal implants containing estradiol-17 beta (E2), ICI or a combination of both compounds. The effects of E2 and ICI on plasma calcium levels were measured and hepatic and testicular gene expression of the three estrogen receptor (ER) subtypes, ER alpha, ER beta a and ER beta b, and the estrogen-responsive genes, vitellogenin II and choriogenin L, were analyzed by semi-quantitative RT-PCR in sea bream. E2 treatment caused an increase in calcium levels in tilapia, while ICI alone had no noticeable effect, as expected. However, pretreatment with ICI synergistically potentiated the effect of E2 on plasma calcium in both species. ICI mimicked some E2 actions in gene expression in sea bream liver upregulating ER alpha, vitellogenin II and choriogenin L, although, unlike E2, it did not downregulate ER beta a and ER beta b. In contrast, no effects of E2 or ICI alone were detected in the expression of ERs in testis, while vitellogenin II and choriogenin L were upregulated by E2 but not ICI. Finally, pretreatment with ICI had a synergistic effect on the hepatic E2 down-regulation of ER beta b, but apparently blocked the ER alpha up-regulation by E2. These results demonstrate that ICI has agonistic effects on several typical estrogenic responses in fish, but its actions are tissue-specific

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

/HUMAN EXPOSURE STUDIES/ ... Following a 14-day, pretrial screening period, 30 eligible postmenopausal volunteers were randomized to receive fulvestrant 250 mg, fulvestrant 125 mg or matched placebo administered as a single intramuscular injection. Two weeks postinjection, volunteers received 2-weeks concurrent exposure to ethinylestradiol 20 ug day(-1). Endometrial thickness was measured before and after the 14-day screening period with further measurements predose (to confirm a return to baseline) and on days 14, 28 and 42 post-treatment with fulvestrant. Pharmacokinetic and safety assessments were performed throughout the trial. Fulvestrant at a dose of 250 mg significantly (P=0.0001) inhibited the estrogen-stimulated thickening of the endometrium compared with placebo. Neither the 125 mg nor 250 mg doses of fulvestrant demonstrated estrogenic effects on the endometrium over the initial 14-day assessment period. ...

/HUMAN EXPOSURE STUDIES/ No adverse effects were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

/EPIDEMIOLOGY STUDIES/ /The authors/ present results from the Austrian Fulvestrant Registry. Three-hundred and fifty patients were included. Time to progression (TTP) was defined as primary endpoint. A multivariate analysis was performed to identify factors significantly associated with TTP. Fulvestrant was administered as first-line therapy in 26%, second-line in 49%, and third-line or beyond in 25%. TTP was median 7 months. /Investigators/ observed a response in 15% of patients and 41% had stable disease >/= 6 months. First-line treatment and non-visceral metastases were associated with longer TTP. One case of pulmonary embolism was reported. Grade 3 toxicities consisted of joint pain (1.4%), nausea (1.4%) and hot flashes (0.3%).

Drug Induced Liver Injury Rank (DILIrank 2.0)

Fulvestrant

Ambiguous-DILI-concern

7

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A two-year carcinogenesis study was conducted in female and male rats, at intramuscular doses of 15 mg/kg/30 days, 10 mg/rat/30 days and 10 mg/rat/15 days. These doses correspond to approximately 1-, 3-, and 5-fold (in females) and 1.3-, 1.3-, and 1.6-fold (in males) the systemic exposure [AUC0-30 days] achieved in women receiving the recommended dose of 250 mg/month. An increased incidence of benign ovarian granulosa cell tumors and testicular Leydig cell tumors was evident, in females dosed at 10 mg/rat/15 days and males dosed at 15 mg/rat/30 days, respectively. Induction of such tumors is consistent with the pharmacology-related endocrine feedback alterations in gonadotropin levels caused by an antiestrogen.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Male rats, 30 days old, were treated with the antiestrogen ICI 182,780 (3-150 days) to determine sequences of events leading to testicular atrophy and infertility. Plasma testosterone and LH concentrations were unchanged. ICI 182,780 induced dilation of efferent ductules as early as 3 days post treatment, and the dilation increased over time, resulting in an overall increase of 200% in tubule diameter. A gradual reduction in height of the ductule epithelium was observed; however, the microvilli height increased up to day 73 but subsequently decreased. A transient increase in lysosomes in nonciliated cells was seen from day 15 to day 100. Testicular weight increased by day 45 and seminiferous tubules were dilated by day 52. These effects on testes persisted until day 100, but on day 150 the weight decreased and severe atrophy was observed. These testicular effects were probably owing to accumulation of fluid following inhibition of reabsorption in the efferent ductules, similar to the ER-alpha knockout mouse. In agreement with this conclusion, there was a decrease in Na+-H+ exchanger-3 mRNA and protein, which is consistent with previous studies showing that ER is required for expression of Na+-H+ exchanger-3 and ultimately fluid reabsorption in the efferent ductules.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... Adult male mice, 30 days old, were injected subcutaneously with ICI 182,780 (5 mg) once per week for 17 weeks. Tissues were fixed by vascular perfusion to study the time responses from day 2 to 125 post treatment. No difference was seen in body weight due to treatment. Testis weight was decreased 18% on day 59 and 21.4% on day 125. Other significant treatment-related effects included the following: 1) dilation of rete testis and efferent ductule lumen; 2) decreased height of the rete testis and efferent ductule epithelium; 3) decreased height of the supranuclear epithelial cytoplasm in efferent ductules; 4) decreased height of the efferent ductule epithelial microvilli, particularly in the proximal ductules; 5) decrease in the PAS-positive granules and endocytotic vesicles in nonciliated epithelial cells of efferent ductules; 6) capping and vesiculation of narrow cells in the initial segment of the epididymis; 7) accumulation of PAS-positive granules in apical cells of the caput epididymis; 8) increase in lysosomal granules in clear cells of the corpus and cauda epididymis; 9) limited induction of atrophic seminiferous tubules and abnormal spermatogenesis; and 10) decreases in the concentration of cauda sperm, progressive sperm motility and decreased fertility. Antiestrogen treatment of the pubertal male mouse resulted in reproductive effects similar to those observed in the estrogen receptor-alpha knockout mouse as early as day 4; however, testis weight did not increase substantially and total atrophy was not observed with extended treatment.

Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. ... /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fulvestrant, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Treatment of breast cancer

THERAP CAT: Antineoplastic (hormonal)

• Pharmaceutical [Ref: https://doi.org/10.1021/cr4002879]

non-polymer PFAS -> Pharmaceuticals -> Active ingredients

Use (kg; approx.) in Germany (2009): >10

For the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.

(7alpha,17beta)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-6-one-3,17-diol (6-keto-fulvestrant); (7alpha,17beta)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(10),6-tetraene-3,17-diol (delta6,7-fulvestrant); (7alpha,17beta)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]nonyl]-estra-1,3,5(10)-triene-3,17-diol (fulvestrant sulfone); (7alpha,17beta)-7-{9-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonylsulfinyl]}-estra-1,3,5(10)-triene-3,17-diol (fulvestrant extended); (7alpha,17beta)-7,7-nonamethylene-bis(estra-1,3,5(10)-triene-3,17-diol (fulvestrant sterol dimer); (7alpha,17beta)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17-diol (fulvestrant beta-isomer)

... estrogen receptor antagonist without any known agonist effects

... a drug treatment of hormone receptor-positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy.