Oxaliplatin (Page 4 of 10)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of oxaliplatin injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • General: angioedema, anaphylactic shock
  • Cardiovascular: QT prolongation leading to ventricular arrhythmias, including fatal torsade de pointes; bradyarrhythmia
  • Neurological: loss of deep tendon reflexes, dysarthria, Lhermitte’s sign, cranial nerve palsies, fasciculations, convulsion
  • Hearing and vestibular system: deafness
  • Infections: septic shock, including fatal outcomes
  • Infusion-related reactions and hypersensitivity reactions: laryngospasm
  • Hepatic and gastrointestinal: severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis, ileus, intestinal obstruction, pancreatitis, sinusoidal obstruction syndrome, perisinusoidal fibrosis which rarely may progress, esophagitis
  • Musculoskeletal and connective tissue: rhabdomyolysis, including fatal outcomes
  • Platelet, bleeding, and clotting disorders: immuno-allergic thrombocytopenia, prolonged prothrombin time and INR in patients receiving anticoagulants
  • Blood disorders: secondary leukemia
  • Red blood cell: hemolytic uremic syndrome, immuno-allergic hemolytic anemia
  • Renal: acute tubular necrosis, acute interstitial nephritis, acute renal failure.
  • Respiratory: interstitial lung diseases (sometimes fatal) and pneumonia (including fatal outcomes)
  • Vision: decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following treatment discontinuation)
  • Injury, poisoning, and procedural complications: fall-related injuries

7 DRUG INTERACTIONS

7.1 Drugs that Prolong the QT Interval

QT interval prolongation and ventricular arrhythmias can occur with oxaliplatin injection [see Warnings and Precautions (5.7)]. Avoid coadministration of oxaliplatin injection with medicinal products with a known potential to prolong the QT interval.

7.2 Use with Nephrotoxic Drugs

Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds [see Clinical Pharmacology (12.3)]. Avoid coadministration of oxaliplatin injection with medicinal products known to cause nephrotoxicity.

7.3 Use with Anticoagulants

Prolonged prothrombin time and INR occasionally associated with hemorrhage have been reported in patients who received oxaliplatin injection with fluorouracil/leucovorin while on anticoagulants [see Warnings and Precautions (5.10), Adverse Reactions (6.2)]. Increase frequency of monitoring in patients who are receiving oxaliplatin injection with fluorouracil/leucovorin and oral anticoagulants.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its direct interaction with DNA, oxaliplatin injection can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin injection. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area (see Data). Advise a pregnant woman of the potential risk to a fetus.

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.

Data

Animal data

Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (GD)1-5 (preimplantation), GD 6-10, or GD 11-16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days GD 6-10 and GD 11-16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days GD 6-10.

8.2 Lactation

Risk Summary

There are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with oxaliplatin injection and for 3 months after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating oxaliplatin injection [see Use in Specific Populations (8.1)].

Contraception

Oxaliplatin Injection can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise female patients of reproductive potential to use effective contraception while receiving oxaliplatin injection and for 9 months after the final dose.

Males

Based on its mechanism action as a genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving oxaliplatin injection and for 6 months after the final dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on animal studies, oxaliplatin injection may impair fertility in males and females [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of oxaliplatin in pediatrics have not been established. Safety and effectiveness were assessed across 4 open-label studies in 235 patients aged 7 months to 22 years with solid tumors.

In a multicenter, open-label, non-comparative, non-randomized study (ARD5531), oxaliplatin was administered to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. The dose limiting toxicity (DLT) was sensory neuropathy at a dose of 110 mg/m2. The main adverse reactions were: paresthesia (60%, grade 3-4: 7%), fever (40%, grade 3-4: 7%), and thrombocytopenia (40%, grade 3-4: 27%). No responses were observed.

In an open-label non-randomized study (DFI7434), oxaliplatin was administered to 26 pediatric patients with metastatic or unresectable solid tumors, mainly neuroblastoma and ganglioneuroblastoma. The DLT was sensory neuropathy at a dose of 160 mg/m2. No responses were observed.

In an open-label, single-agent study (ARD5021), oxaliplatin was administered to 43 pediatric patients with recurrent or refractory embryonal CNS tumors. The most common adverse reactions reported were: leukopenia (67%, grade 3-4: 12%), anemia (65%, grade 3-4: 5%), thrombocytopenia (65%, grade 3-4: 26%), vomiting (65%, grade 3-4: 7%), neutropenia (58%, grade 3-4: 16%), and sensory neuropathy (40%, grade 3-4: 5%).

In an open-label single-agent study (ARD5530), oxaliplatin was administered to 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, Ewing sarcoma or peripheral PNET, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, Brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors. The most common adverse reactions reported were: sensory neuropathy (52%, grade 3-4: 12%), thrombocytopenia (37%, grade 3-4: 17%), anemia (37%, grade 3-4: 9%), vomiting (26%, grade 3-4: 4%), increased ALT (24%, grade 3-4: 6%), increased AST (24%, grade 3-4: 2%), and nausea (23%, grade 3-4: 3%).

The pharmacokinetic parameters of ultrafiltrable platinum were evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h (%CV, 41%). Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 ± 0.24 mcg/mL, AUC0-48h of 7.52 ± 5.07 mcg∙h/mL and AUCinf of 8.83 ± 1.57 mcg∙h/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10 ± 0.43 mcg/mL, AUC0-48h of 9.74 ± 2.52 mcg∙h/mL and AUCinf of 17.3 ± 5.34 mcg∙h/mL at 130 mg/m2 of oxaliplatin.

8.5 Geriatric Use

In the adjuvant treatment trial [see Clinical Studies (14.1)] , 400 patients who received oxaliplatin injection with fluorouracil/leucovorin were greater than or equal to 65 years. The effect of oxaliplatin injection in patients greater than or equal to 65 years was not conclusive. Patients greater than or equal to 65 years receiving oxaliplatin injection experienced more diarrhea and grade 3-4 neutropenia (45% vs 39%) compared to patients less than 65 years.

In the previously untreated advanced colorectal cancer trial [see Clinical Studies (14.2)] , 99 patients who received oxaliplatin injection with fluorouracil and leucovorin were greater than or equal to 65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the greater than or equal to 65 years patients as in the overall study population. Adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope.

In the previously treated advanced colorectal cancer trial [see Clinical Studies (14.3)] , 55 patients who received oxaliplatin injection with fluorouracil and leucovorin were greater than or equal to 65 years. No overall differences in effectiveness were observed between these patients and younger adults. Adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, and fatigue.

No significant effect of age on the clearance of ultrafiltrable platinum has been observed [see Clinical Pharmacology (12.3)].

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