Ofev (Page 3 of 8)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of OFEV. 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. The following adverse reactions have been identified during postapproval use of OFEV: drug-induced liver injury [see Warnings and Precautions (5.2)] , non-serious and serious bleeding events, some of which were fatal [see Warnings and Precautions (5.6)], proteinuria [see Warnings and Precautions (5.8)] , pancreatitis, thrombocytopenia, rash, pruritus.

7 DRUG INTERACTIONS

7.1 P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers

Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4 [see Clinical Pharmacology (12.3)]. Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib [see Clinical Pharmacology (12.3)]. In such cases, patients should be monitored closely for tolerability of OFEV. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV [see Dosage and Administration (2.4)].

Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John’s wort) with OFEV should be avoided as these drugs may decrease exposure to nintedanib [see Clinical Pharmacology (12.3)].

7.2 Anticoagulants

Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary [see Warnings and Precautions (5.6)].

7.3 Pirfenidone

In a multiple-dose study conducted to assess the pharmacokinetic effects of concomitant treatment with nintedanib and pirfenidone, the coadministration of nintedanib with pirfenidone did not alter the exposure of either agent [see Clinical Pharmacology (12.3)]. Therefore, no dose adjustment is necessary during concomitant administration of nintedanib with pirfenidone.

7.4 Bosentan

Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)] , OFEV can cause fetal harm when administered to a pregnant woman. There are no data on the use of OFEV during pregnancy. In animal studies of pregnant rats and rabbits treated during organogenesis, nintedanib caused embryo-fetal deaths and structural abnormalities at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose [see Data]. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage in clinically recognized pregnancies is 15% to 20%.

Data

Animal Data

In animal reproduction toxicity studies, nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). Malformations included abnormalities in the vasculature, urogenital, and skeletal systems. Vasculature anomalies included missing or additional major blood vessels. Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (e.g., hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified). In some fetuses, organs in the urogenital system were missing. In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day). Nintedanib decreased post-natal viability of rat pups during the first 4 post-natal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

8.2 Lactation

Risk Summary

There is no information on the presence of nintedanib in human milk, the effects on the breast-fed infant or the effects on milk production. Nintedanib and/or its metabolites are present in the milk of lactating rats [see Data]. Because of the potential for serious adverse reactions in nursing infants from OFEV, advise women that breastfeeding is not recommended during treatment with OFEV.

Data

Milk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites.

8.3 Females and Males of Reproductive Potential

Based on findings from animal studies and its mechanism of action, OFEV can cause fetal harm when administered to a pregnant woman and may reduce fertility in females of reproductive potential [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1, 12.3), and Nonclinical Toxicology (13.1)]. Counsel patients on pregnancy prevention and planning.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to treatment with OFEV and during treatment as appropriate [see Dosage and Administration (2.1), Warnings and Precautions (5.4), and Use in Specific Populations (8.1)].

Contraception

OFEV can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV. Advise females of reproductive potential to use highly effective contraception at initiation of, during treatment, and for at least 3 months after taking the last dose of OFEV. Nintedanib does not change the exposure to oral contraceptive containing ethinylestradiol and levonorgestrel in patients with SSc-ILD. However, the efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced. Advise women taking oral hormonal contraceptives experiencing these conditions to use alternative highly effective contraception.

Infertility

Based on animal data, OFEV may reduce fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of subjects in phase 2 and 3 clinical studies of OFEV in IPF (Study 1, Study 2, and Study 3), 61% were 65 and over, while 16% were 75 and over. In the chronic fibrosing ILDs with a progressive phenotype clinical study (Study 5), 61% were 65 and over, while 19% were 75 and older. In SSc-ILD (Study 4), 21.4% were 65 and over, while 1.9% were 75 and older. In phase 3 studies, no overall differences in effectiveness were observed between subjects who were 65 and over and younger subjects; no overall differences in safety were observed between subjects who were 65 and over or 75 and over and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

Nintedanib is predominantly eliminated via biliary/fecal excretion (greater than 90%). In a PK study performed in patients with hepatic impairment (Child Pugh A, Child Pugh B), exposure to nintedanib was increased [see Clinical Pharmacology (12.3)]. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily [see Dosage and Administration (2.3)]. Monitor for adverse reactions and consider treatment interruption, or discontinuation for management of adverse reactions in these patients [see Dosage and Administration (2.4)]. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended [see Warnings and Precautions (5.1)].

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