Ofev

Uses

• Ofev is used for adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF).
• Ofev is used for adults for the treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype.
• Ofev is used for adults for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD).
• Ofev is used for combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumor histology after first-line chemotherapy.

Ofev is also used to associated treatment for these conditions: Idiopathic Pulmonary Fibrosis (IPF), Respiratory Function Impaired, Locally advanced Non-Small Cell Lung Cancer (NSCLC) caused by Adenocarcinoma, Locally recurrent Non-Small Cell Lung Cancer (NSCLC) caused by Adenocarcinoma, Metastatic Non-Small Cell Lung Cancer (NSCLC) caused by Adenocarcinoma

How Ofev works

Ofev is a small molecule, competitive, triple angiokinase inhibitor that targets multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Many of these RTKs are implicated in lung fibrosis and tumour angiogenesis, so nintedanib is therefore used in the treatment of proliferative diseases such as idiopathic pulmonary fibrosis, non-small cell lung cancer, and systemic sclerosis-associated interstitial lung disease. The specific RTKs that nintedanib inhibits are platelet-derived growth factor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, and Fns-Like tyrosine kinase-3 (FLT3). Ofev binds to the ATP-binding pocket of these receptors and inhibits their activity, thereby blocking signalling cascades that result in the proliferation and migration of lung fibroblasts. Ofev also inhibits kinase signalling pathways in various cells within tumour tissues, including endothelial cells, pericytes, smooth muscle cells, and cells contributing to angiogenesis, culminating in an inhibition of cell proliferation and apoptosis of affected tumour cells.

In addition to RTK inhibition, nintedanib also prevents the actions of the nRTKs Lck, Lyn, and Src. The contribution of the inhibition of Lck and Lyn towards the therapeutic efficacy of nintedanib is unclear, but inhibition of the Src pathway by nintedanib has been shown to reduce lung fibrosis.

Dosage

Ofev dosage

Treatment with Ofev should be initiated by physicians experienced in the diagnosis and treatment of IPF.

Posology: The recommended dose is 150 mg Ofev twice daily administered approximately 12 hours apart. The 100 mg twice daily dose is only recommended to be used in patients who do not tolerate the 150 mg twice daily dose. If a dose is missed, administration should resume at the next scheduled time at the recommended dose. If a dose is missed the patient should not take an additional dose. The recommended maximum daily dose of 300 mg should not be exceeded.

For NSCLC:

• The recommended dose of nintedanib is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle.
• Ofev must not be taken on the same day of docetaxel chemotherapy administration (= day 1). If a dose of nintedanib is missed, administration should resume at the next scheduled time at the recommended dose. The individual daily doses of nintedanib should not be increased beyond the recommended dose to make up for missed doses. The recommended maximum daily dose of 400 mg should not be exceeded.
• Patients may continue therapy with nintedanib after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs.
• Dose adjustments: In addition to symptomatic treatment if applicable, the management of adverse reactions to Ofev could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. Ofev treatment may be resumed at the full dose (150 mg twice daily) or a reduced dose (100 mg twice daily). If a patient does not tolerate 100 mg twice daily, treatment with Ofev should be discontinued.
• In case of interruptions due to aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations > 3x upper limit of normal (ULN), once transaminases have returned to baseline values, treatment with Ofev may be reintroduced at a reduced dose (100 mg twice daily) which subsequently may be increased to the full dose (150 mg twice daily).

Ofev is for oral use. The capsules should be taken with food, swallowed whole with water, and should not be chewed or crushed.

Side Effects

Summary of the safety profile: Ofev has been studied in clinical trials of 1,529 patients suffering from IPF. The safety data provided in the following are based on the two Phase III, randomized, double-blind, placebo-controlled studies in 1,061 patients comparing treatment with Ofev 150 mg twice daily to placebo for 52 weeks (INPULSIS-1 and INPULSIS-2) and based on data observed during the post-marketing period.

The most frequently reported adverse reactions associated with the use of Ofev included diarrhea, nausea and vomiting, abdominal pain, decreased appetite, weight decreased and hepatic enzyme increased.

Tabulated list of adverse reactions: The below table provides a summary of the adverse reactions by MedDRA System Organ Class (SOC) and frequency category.

Below table summarizes the frequencies of adverse drug reactions (ADRs) that were reported in the Ofev group (638 patients) pooled from the two placebo-controlled Phase III clinical trials of 52 weeks duration or from the post-marketing period.

Frequency categories are defined using the following convention: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

Toxicity

Experience with nintedanib overdose is limited, but patients who inadvertently received higher-than-intended doses during initial trials experienced adverse effects consistent with the known safety profile of nintedanib, for example elevated liver enzymes and significant gastrointestinal effects.

There are no specific guidelines for the treatment of nintedanib overdose - in this case, therapy should be interrupted and general supportive measures employed as indicated.

Precaution

Diarrhoea: In the INPULSIS trials, diarrhoea was the most frequent gastro-intestinal adverse reaction reported in 62.4% versus 18.4% of patients treated with Ofev and placebo, respectively. In most patients the adverse reaction was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhoea led to dose reduction in 10.7% of the patients and to discontinuation of Ofev in 4.4% of the patients in clinical trials. Serious cases of diarrhoea leading to dehydration and electrolyte disturbances have been reported in the post-marketing. Patients should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require treatment interruption. Ofev treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with Ofev should be discontinued.

Nausea and vomiting: Nausea and vomiting were frequently reported gastrointestinal adverse reactions. In most patients with nausea and vomiting, the event was of mild to moderate intensity. Nausea led to discontinuation of Ofev in 2.0% of patients. Vomiting led to discontinuation in 0.8% of the patients. If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction or treatment interruption may be required. The treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe symptoms therapy with Ofev should be discontinued.

Hepatic function: The safety and efficacy of Ofev has not been studied  in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore, treatment with Ofev is not recommended in such patients. Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). Patients with mild hepatic impairment (Child Pugh A) should be treated with a reduced dose of Ofev. Cases of drug-induced liver injury have been observed with Ofev treatment, including severe liver injury with fatal outcome. The majority of hepatic events occur within the first three months of treatment. Therefore, hepatic transaminase and bilirubin levels should be investigated before treatment initiation and during the first month of treatment with Ofev. Patients should then be monitored at regular intervals during the subsequent two months of treatment and periodically thereafter, e.g. at each patient visit or as clinically indicated. Elevations of liver enzymes (ALT, AST, ALKP, gamma-glutamyl-transferase (GGT) and bilirubin were reversible upon dose reduction or interruption in the majority of cases. If transaminase (AST or ALT) elevations > 3x ULN are measured, dose reduction or interruption of the therapy with Ofev is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with Ofev may be resumed at the full dose (150 mg twice daily) or reintroduced at a reduced dose (100 mg twice daily) which subsequently may be increased to the full dose. If any liver test elevations are associated with clinical signs or symptoms of liver injury, e.g. jaundice, treatment with Ofev should be permanently discontinued. Alternative causes of the liver enzyme elevations should be investigated.

Patients with low body weight (<65 kg), Asian and female patients have a higher risk of elevations of liver enzymes. Ofev exposure increased linearly with patient age, which may also result in a higher risk of developing liver enzyme elevations. Close monitoring is recommended in patients with these risk factors.

Renal Function: Cases of renal impairment/failure, in some cases with fatal outcome, have been reported with Ofev use. Patients should be monitored during Ofev therapy, with particular attention to those patients exhibiting risk factors for renal impairment/failure. In case of renal impairment/failure, therapy adjustment should be considered.

Haemorrhage: Vascular endothelial growth factor receptor (VEGFR) inhibition might be associated with an increased risk of bleeding. In the INPULSIS trials with Ofev, the frequency of patients who experienced bleeding AEs was slightly higher in the Ofev arm (10.3%) than in the placebo arm (7.8%). Non-serious epistaxis was the most frequent bleeding event. Serious bleeding events occurred with low and similar frequencies in the 2 treatment groups (placebo: 1.4%; Ofev: 1.3%). Patients at known risk for bleeding including patients with inherited predisposition to bleeding or patients receiving a full dose of anti-coagulative treatment were not included in the INPULSIS studies. Non-serious and serious bleeding events, some of which were fatal, have been reported in the post-marketing period (including patients with or without anticoagulant therapy or other drugs that could cause bleeding). Therefore, these patients should only be treated with Ofev if the anticipated benefit outweighs the potential risk. Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous organ systems, with the most frequent being gastrointestinal.

Arterial thromboembolic events: Patients with a recent history of myocardial infarction or stroke were excluded from the INPULSIS trials. Arterial thromboembolic events were infrequently reported: in 0.7% of patients in the placebo and 2.5% in the Ofev treated group. While adverse events reflecting ischemic heart disease were balanced between the Ofev and placebo groups, a higher percentage of patients experienced myocardial infarctions in the Ofev group (1.6%) compared to the placebo group (0.5%). Caution should be used when treating patients at higher cardiovascular risk including known coronary artery disease. Treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischemia.

Venous thromboembolism: In the INPULSIS trials no increased risk of venous thromboembolism was observed in Ofev treated patients. Due to the mechanism of action of Ofev patients might have an increased risk of thromboembolic events.

Gastrointestinal perforations: In the INPULSIS trials, the frequency of patients with perforation was very low in both treatment groups: 0% placebo, 0.3% Ofev (involving two patients). Due to the mechanism of action of Ofev patients might have an increased risk of gastrointestinal perforation. Cases of gastrointestinal perforations, some of which were fatal, have been reported in the post-marketing period. Particular caution should be exercised when treating patients with previous abdominal surgery, previous history of peptic ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs. Ofev should only be initiated at least 4 weeks after abdominal surgery. Therapy with Ofev should be permanently discontinued in patients who develop gastrointestinal perforation.

Hypertension: Administration of Ofev may increase blood pressure. Systemic blood pressure should be measured periodically and as clinically indicated.

Wound healing complication: No increased frequency of impaired wound healing was observed in the INPULSIS trials. Based on the mechanism of action Ofev may impair wound healing. No dedicated studies investigating the effect of Ofev on wound healing were performed. Treatment with Ofev should therefore only be initiated or – in case of perioperative interruption – resumed based on clinical judgement of adequate wound healing.

Co-administration with Pirfenidone: In a dedicated pharmacokinetic study, concomitant treatment of Ofev with Pirfenidone was investigated in patients with IPF. Based on these results, there is no evidence of a relevant pharmacokinetic drug-drug interaction between Ofev and Pirfenidone when administered in combination. In view of the limited number of patients, this study detected only the most frequent adverse events and showed an increase in gastrointestinal adverse events and a trend toward increased hepatic adverse events. Given the similarity in safety profiles for both medicinal products, additive adverse events, including gastrointestinal and hepatic adverse events, may be expected. The benefit-risk balance of concomitant treatment with Pirfenidone has not been established.

Effect on QT interval: No evidence of QT prolongation was observed for Ofev in the clinical trial programme. As some other tyrosine kinase inhibitors are known to exert an effect on QT, caution should be exercised when administered Ofev in patients who may develop QTc prolongation.

Allergic reaction: Dietary soya products are known to cause allergic reactions including severe anaphylaxis in persons with soya allergy. Patients with known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations.

Interaction

P-glycoprotein (P-gp): Ofev is a substrate of P-gp. Co-administration with the potent P-gp inhibitor ketoconazole increased exposure to Ofev 1.61-fold based on AUC and 1.83-fold based on Cmax in a dedicated drug-drug interaction study. In a drug-drug interaction study with the potent P-gp inducer rifampicin, exposure to Ofev decreased to 50.3% based on AUC and to 60.3% based on Cmax upon co-administration with rifampicin compared to administration of Ofev alone. If co-administered with Ofev, potent P-gp inhibitors (e.g. ketoconazole, erythromycin or cyclosporine) may increase exposure to Ofev. In such cases, patients should be monitored closely for tolerability of Ofev. Management of side effects may require interruption, dose reduction, or discontinuation of therapy with Ofev. Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease exposure to Ofev. Selection of an alternate concomitant medicinal product with no or minimal P-gp induction potential should be considered.

Cytochrome (CYP)-enzymes: Only a minor extent of the biotransformation of Ofev consisted of CYP pathways. Ofev and its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in preclinical studies. The likelihood of drug-drug interactions with Ofev based on CYP metabolism is therefore considered to be low.

Co-administration with other medicinal products: The potential for interactions of Ofev with hormonal contraceptives was not explored.

Food Interaction

• Take with food. Co-administration with food improves absorption.

[Moderate] ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of nintedanib.

After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions.

Absorption was also delayed, as indicated by an increase in the median time to reach maximum plasma concentration (Tmax) from 2 hours in the fasted state to approximately 4 hours under fed conditions, irrespective of the type of food ingested.

MANAGEMENT: Ofev should be administered with food.

Ofev Drug Interaction

Moderate: diltiazem, apixabanUnknown: fluticasone / salmeterol, naproxen, diphenhydramine, bumetanide, sulfamethoxazole / trimethoprim, formoterol / mometasone, metoprolol, metoprolol, guaifenesin, esomeprazole, acetaminophen, bifidobacterium infantis / lactobacillus acidophilus, bioflavonoids, sotalol, fluticasone / umeclidinium / vilanterol, cyanocobalamin, pyridoxine, cholecalciferol

Ofev Disease Interaction

Moderate: lung toxicity, arterial thromboembolism, bleeding, gastrointestinal perforation, hepatic impairment, renal impairment, smoking

Volume of Distribution

Ofev appears to follow biphasic disposition kinetics - the observed volume of distribution following intravenous administration is 1050 L, indicating extensive distribution into peripheral tissues. In rats, nintedanib was shown to rapidly and homogeneously distribute into peripheral tissues with the exception of the CNS, suggestive of an inability of nintedanib to cross the blood-brain barrier.

Elimination Route

The absolute bioavailability of nintedanib is low at approximately 4.7%, likely owing to substantial first-pass metabolism and the effects of p-glycoprotein (P-gp) transporters. T_max following oral administration is reached after approximately 2 hours in fasted patients and approximately 4 hours in fed patients, regardless of the food consumed. Administration of nintedanib following a high-fat, high-calorie meal resulted in an increase in C_max by approximately 15% and an increase in AUC by approximately 20%. Age, body weight, and smoking status have been found to alter exposure to nintedanib, but these effects are not significant enough to warrant dose alterations.

Half Life

The terminal elimination half-life of nintedanib is approximately 10-15 hours. In patients with idiopathic pulmonary fibrosis, the effective half-life of nintedanib has been estimated to be approximately 9.5 hours.

Clearance

Ofev is has a high total plasma clearance of approximately 1390 mL/min and a renal clearance of 20 mL/min.

Elimination Route

Ofev is eliminated primarily via fecal and biliary excretion, with 93.4% of radio labelled nintedanib found in feces within 120 hours following administration. Renal clearance accounts for a small portion of nintedanib's elimination, approximately 0.65% of the total dose, and excretion of unchanged nintedanib 48 hours after oral and intravenous doses was 0.05% and 1.4%, respectively.

Pregnancy & Breastfeeding use

Women of childbearing potential/Contraception: Ofev may cause foetalharm in humans. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Ofev. They should be advised to use adequate contraception during and at least 3 months after the last dose of Ofev. Since the effect of Ofev on the metabolism and efficacy of hormonal contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy.

Pregnancy: There is no information on the use of Ofev in pregnant women, but pre-clinical studies in animals have shown reproductive toxicity of this active substance. As Ofev may cause foetal harm also in humans, it must not be used during pregnancy. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy with Ofev. If the patient becomes pregnant while receiving Ofev, she should be apprised of the potential hazard to the foetus. Termination of the treatment with Ofev should be considered.

Lactation: There is no information on the excretion of Ofev and its metabolites in human milk. Pre-clinical studies showed that small amounts of Ofev and its metabolites (≤ 0.5% of the administered dose) were secreted into milk of lactating rats. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Ofev.

Fertility: Based on preclinical investigations there is no evidence for impairment of male fertility. From subchronic and chronic toxicity studies, there is no evidence that female fertility in rats is impaired at a systemic exposure level comparable with that at the maximum recommended human dose (MRHD) of 150 mg twice daily.

Contraindication

Hypersensitivity to Ofev, to peanut or soya, or to any of the excipients.

Storage Condition

Store in a cool and dry place, protected from light. Do not store above 25°C.

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