Denine 100 mg/150 mg Capsules

4.4 Special Warnings and Precautions for use

Gastrointestinal disorders
Diarrhoea
In the clinical trials, diarrhoea was the most frequent gastro-intestinal adverse reaction reported. In most patients, the adverse reaction was of mild to moderate intensity and occurred within the first 3 months of treatment.
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 dose reduction or treatment interruption. Nintedanib treatment may be resumed at a reduced dose or at the full dose. In case of persisting severe diarrhoea despite symptomatic treatment, therapy with Nintedanib 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.
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 or at the full dose. In case of persisting severe symptoms therapy with nintedanib should be discontinued.

Hepatic function
The safety and efficacy of nintedanib has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore, treatment with Nintedanib is not recommended in such patients. Based on increased exposure, the risk for adverse reactions may be increased in patients with mild hepatic impairment (Child Pugh A). Adult patients with mild hepatic impairment (Child Pugh A) should be treated with a reduced dose of nintedanib.
Cases of drug-induced liver injury have been observed with nintedanib 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 nintedanib. 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, blood alkaline phosphatase (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 > 3× ULN are measured, dose reduction or interruption of the therapy with nintedanib is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with nintedanib may be resumed at the full dose or reintroduced at a reduced dose 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 Nintedanib should be permanently discontinued. Alternative causes of the liver enzyme elevations should be investigated.
Adult patients with low body weight (< 65 kg), Asian and female patients have a higher risk of elevations of liver enzymes. Nintedanib 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 nintedanib use. Patients should be monitored during nintedanib 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. Patients at known risk for bleeding including patients with inherited predisposition to bleeding or patients receiving a full dose of anticoagulative treatment were not included in the clinical trials. 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 medicinal products that could cause bleeding). Therefore, these patients should only be treated with Nintedanib if the anticipated benefit outweighs the potential risk.

Arterial thromboembolic events
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.

Aneurysms and artery dissections
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Nintedanib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

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

Gastrointestinal perforations and ischaemic colitis
Due to the mechanism of action of nintedanib, patients might have an increased risk of gastrointestinal perforations.
Cases of gastrointestinal perforations and cases of ischaemic colitis, 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.
Nintedanib should only be initiated at least 4 weeks after abdominal surgery. Therapy with Nintedanib should be permanently discontinued in patients who develop gastrointestinal perforation or ischaemic colitis. Exceptionally, Nintedanib can be reintroduced after complete resolution of ischaemic colitis and careful assessment of patient's condition and other risk factors.

Nephrotic range proteinuria and thrombotic microangiopathy
Very few cases of nephrotic range proteinuria with or without renal function impairment have been reported post marketing. Histological findings in individual cases were consistent with glomerular microangiopathy with or without renal thrombi. Reversal of the symptoms has been observed after Nintedanib was discontinued, with residual proteinuria in some cases. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.
VEGF pathway inhibitors have been associated with thrombotic microangiopathy (TMA), including very few case reports for nintedanib. If laboratory or clinical findings associated with TMA occur in a patient receiving nintedanib, treatment with nintedanib should be discontinued and thorough evaluation for TMA should be completed.

Posterior reversible encephalopathy syndrome (PRES)
Some cases of posterior reversible encephalopathy syndrome (PRES) have been reported post-marketing. PRES is a neurological disorder (confirmed with magnetic resonance imaging) which can present with headache, hypertension, visual disturbances, seizure, lethargy, confusion and other visual and neurologic disturbances, and can be fatal. PRES has been reported with other VEGF inhibitors.
If PRES is suspected, nintedanib treatment must be discontinued. Reinitiating nintedanib therapy in patients previously experiencing PRES is not known and should be left to the physician's recommendation.

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

Pulmonary hypertension
Data on the use of Nintedanib in patients with pulmonary hypertension is limited. Nintedanib should not be used in patients with severe pulmonary hypertension. Close monitoring is recommended in patients with mild to moderate pulmonary hypertension.

Wound healing complication
No increased frequency of impaired wound healing was observed in the clinical trials. Based on the mechanism of action nintedanib may impair wound healing. No dedicated studies investigating the effect of nintedanib on wound healing were performed. Treatment with Nintedanib 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 nintedanib with pirfenidone was investigated in patients with IPF. Based on these results, there is no evidence of a relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when administered in combination. Given the similarity in safety profiles for both medicinal products, additive adverse reactions, 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 nintedanib in the clinical trial programme. As some other tyrosine kinase inhibitors are known to exert an effect on QT, caution should be exercised when nintedanib is administered in patients who may develop QTc prolongation.

Paediatric population
Data on the use of nintedanib in paediatric patients is limited to a small subset of fibrosing interstitial lung diseases. This subset does not cover all aetiologies associated with progressive fibrosing interstitial lung disease in paediatric patients.
There is greater uncertainty regarding the magnitude of treatment benefit in paediatric patients than in adults. The above precautions for adult patients must also be followed for paediatric patients.
For specific dose reduction recommendations in paediatric population, see Table 1.
Bone development and growth
Reversible epiphyseal growth plate alterations were observed in preclinical studies. In the paediatric clinical trial, significant reductions in growth rate were not observed while receiving nintedanib. However, long term safety data in paediatric patients are not available. Growth must be regularly monitored, and evaluation of epiphyseal growth plate alteration via annual bone imaging is recommended in patients with open epiphyses. Treatment interruption should be considered in patients who develop signs of growth impairment or epiphyseal growth plates alterations.
Tooth development disorders
Tooth development disorders were observed in preclinical studies. In the paediatric clinical trial, the risk of tooth development disorders was not confirmed. As a precautionary measure, oral dental examination must regularly be performed at least every 6 months until development of dentition is completed.

4.5 Drug Interactions

P-glycoprotein (P-gp)
Nintedanib is a substrate of P-gp. Co-administration with the potent P-gp inhibitor ketoconazole increased exposure to nintedanib 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 nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmax upon co-administration with rifampicin compared to administration of nintedanib alone. If co-administered with Nintedanib, potent P-gp inhibitors (e.g. ketoconazole, erythromycin or cyclosporine) may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of nintedanib. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with nintedanib.
Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John's Wort) may decrease exposure to nintedanib. 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 nintedanib consisted of CYP pathways. Nintedanib 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 nintedanib based on CYP metabolism is therefore considered to be low.

Co-administration with other medicinal products
Co-administration of nintedanib with oral hormonal contraceptives did not alter the pharmacokinetics of oral hormonal contraceptives to a relevant extent. Co-administration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.

Paediatric population
Interaction studies have only been performed in adults.

4.6 Use in special populations

Women of childbearing potential / Contraception
Nintedanib may cause foetal harm in humans. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Nintedanib and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of nintedanib. Nintedanib does not relevantly affect the plasma exposure of ethinylestradiol and levonorgestrel. The efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhoea or other conditions where the absorption may be affected. Women taking oral hormonal contraceptives experiencing these conditions should be advised to use an alternative highly effective contraceptive measure.

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

Breast-feeding
There is no information on the excretion of nintedanib and its metabolites in human milk. Pre-clinical studies showed that small amounts of nintedanib 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 Nintedanib.

Fertility
Based on preclinical investigations there is no evidence for impairment of male fertility. From sub chronic 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.

4.7 Effects on Ability to Drive and Use Machines

Nintedanib has minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines during treatment with nintedanib.

4.8 Undesirable Effects

Table 2:

Reporting of Suspected Adverse Reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to: medico@zorvia.com
By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There is no specific antidote or treatment for nintedanib overdose. Two patients in the oncology programme had an overdose of maximum 600 mg twice daily up to eight days. Observed adverse reactions were consistent with the known safety profile of nintedanib, i.e. increased liver enzymes and gastrointestinal symptoms. In case of overdose, treatment should be interrupted and general supportive measures initiated as appropriate.

5.0 Pharmacological Properties

5.1 Mechanism of action

Nintedanib is a small molecule tyrosine kinase inhibitor including the receptors platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1‑3, and VEGFR 1‑3. In addition, nintedanib inhibits Lck (lymphocyte-specific tyrosine-protein kinase), Lyn (tyrosine-protein kinase lyn), Src (proto-oncogene tyrosine-protein kinase src), and CSF1R (colony stimulating factor 1 receptor) kinases. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these kinases and blocks the intracellular signalling cascades, which have been demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling in interstitial lung diseases.

5.2 Pharmacodynamic properties

In in vitro studies using human cells nintedanib has been shown to inhibit processes assumed to be involved in the initiation of the fibrotic pathogenesis, the release of pro-fibrotic mediators from peripheral blood monocytic cells and macrophage polarisation to alternatively activated macrophages. Nintedanib has been demonstrated to inhibit fundamental processes in organ fibrosis, proliferation and migration of fibroblasts and transformation to the active myofibroblast phenotype and secretion of extracellular matrix. In animal studies in multiple models of IPF, SSc/SSc-ILD, rheumatoid arthritis-associated-(RA-)ILD and other organ fibrosis, nintedanib has shown anti-inflammatory effects and anti-fibrotic effects in the lung, skin, heart, kidney, and liver. Nintedanib also exerted vascular activity. It reduced dermal microvascular endothelial cell apoptosis and attenuated pulmonary vascular remodelling by reducing the proliferation of vascular smooth muscle cells, the thickness of pulmonary vessel walls and percentage of occluded pulmonary vessels.

5.3 Pharmacokinetic properties

Absorption
Nintedanib reached maximum plasma concentrations approximately 2‑4 h after oral administration as soft gelatine capsule under fed conditions (range 0.5‑8 h). The absolute bioavailability of a 100 mg dose was 4.69% (90% CI: 3.615‑6.078) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism. Nintedanib exposure increased dose-proportionally in the dose range of 50-450 mg once daily and 150-300 mg twice daily. Steady state plasma concentrations were achieved within one week of dosing at the latest.
After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (CI: 95.3‑152.5%) and absorption was delayed (median tmax fasted: 2.00 h; fed: 3.98 h). In an in vitro study, mixing nintedanib capsules with a small amount of apple sauce or chocolate pudding for up to 15 minutes did not have any impact on the pharmaceutical quality. Swelling and deformation of the capsules due to the water uptake of the gelatin capsule shell was observed with longer exposure time to the soft food. Therefore, taking the capsules with soft food would not be expected to alter the clinical effect when taken immediately.
In a single-dose relative bioavailability study of nintedanib in healthy male adult subjects, administered either as one 100 mg soft gelatin capsule or as four 25 mg soft gelatin capsules, bioavailability was similar in both treatments.

Distribution
Nintedanib follows at least bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution (Vss: 1 050 L, 45.0% gCV) was observed.
The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.869.

Biotransformation
The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by uridine 5'-diphospho-glucuronosyltransferase enzymes (UGT) enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide.
Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP 3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human ADME study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.
Nintedanib, BIBF 1202, and BIBF 1202 glucuronide did not inhibit or induce CYP enzymes in preclinical studies, either. Drug-drug interactions between nintedanib and CYP substrates, CYP inhibitors, or CYP inducers are therefore not expected.

Elimination
Total plasma clearance after intravenous infusion was high (CL: 1 390 mL/min, 28.8% gCV). Urinary excretion of the unchanged active substance within 48 h was about 0.05% of the dose (31.5% gCV) after oral and about 1.4% of the dose (24.2% gCV) after intravenous administration; the renal clearance was 20 mL/min (32.6% gCV). The major route of elimination of drug related radioactivity after oral administration of [14C] nintedanib was via faecal/biliary excretion (93.4% of dose, 2.61% gCV). The contribution of renal excretion to the total clearance was low (0.649% of dose, 26.3% gCV). The overall recovery was considered complete (above 90%) within 4 days after dosing. The terminal half-life of nintedanib was between 10 and 15 h (gCV % approximately 50%).

6.0 Nonclinical Properties

6.1 Animal Toxicology or Pharmacology

General toxicology
Single dose toxicity studies in rats and mice indicated a low acute toxic potential of nintedanib. In repeat dose toxicology studies in young rats, irreversible changes of enamel and dentin were observed in the continuously fast-growing incisors, but not in premolars or molars. In addition, thickening of epiphyseal growth plates during bone growth phases was observed and was reversible after discontinuation. These changes are known from other VEGFR-2 inhibitors and can be considered class effects.
Diarrhoea and vomiting accompanied by reduced food consumption and loss of body weight were observed in toxicity studies in non-rodents.
There was no evidence of liver enzyme increases in rats, dogs, and cynomolgus monkeys. Mild liver enzyme increases, which were not due to serious adverse effects such as diarrhoea were only observed in rhesus monkeys.

Reproduction toxicity
In rats, embryo-foetal lethality and teratogenic effects were observed at exposure levels below human exposure at the MRHD of 150 mg twice daily. Effects on the development of the axial skeleton and on the development of the great arteries were also noted at subtherapeutic exposure levels.
In rabbits, embryo-foetal lethality and teratogenic effects were observed at an exposure approximately 3 times higher than at the MRHD but equivocal effects on the embryo-foetal development of the axial skeleton and the heart were noted already at an exposure below that at the MRHD of 150 mg twice daily.
In a pre- and postnatal development study in rats, effects on pre- and post-natal development were seen at an exposure below the MRHD.
A study of male fertility and early embryonic development up to implantation in rats did not reveal effects on the male reproductive tract and male fertility.
In rats, small amounts of radiolabelled nintedanib and/or its metabolites were excreted into the milk (≤ 0.5% of the administered dose). From the 2-year carcinogenicity studies in mice and rats, there was no evidence for a carcinogenic potential of nintedanib. Genotoxicity studies indicated no mutagenic potential for nintedanib.

7. Description

Denine capsules contain nintedanib, a kinase inhibitor.
Molecular Weight: 649.76 g/mol.
Chemical Name: 1H-Indole-6-carboxylic acid, 2,3- dihydro-3-[[[4-[methyl[(4-methyl-1- piperazinyl) acetyl] amino] phenyl]amino] phenylmethylene] -2-oxo-,methyl ester, (3Z)-, ethanesulfonate (1:1).
Molecular Formula: C31H33N5O4·C2H6O3S.
structural formula

8. Pharmaceutical particulars

8.1 Incompatibilities
Not applicable
8.2 Shelf-Life
Refer on pack
8.3 Packaging Information
As per carton
8.4 Storage and Handling Instructions
Store below 25°C, excursion permitted from 15°C to 30°C. Protect from light and moisture.
Keep out of reach of children.

9.0 Patient Counselling Information

Elevated Liver Enzymes and Drug-Induced Liver Injury
Advise patients that they will need to undergo liver function testing periodically. Advise patients to immediately report any symptoms of a liver problem (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleed or bruise more easily than normal, lethargy, loss of appetite).

Gastrointestinal Disorders
Inform patients that gastrointestinal disorders such as diarrhea, nausea, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received nintedanib. Advise patients that their healthcare provider may recommend hydration, antidiarrheal medications (e.g., loperamide), or anti-emetic medications to treat these side effects. Temporary dosage reductions or discontinuations may be required. Instruct patients to contact their healthcare provider at the first signs of diarrhea or for any severe or persistent diarrhea, nausea, or vomiting.

Embryo-Fetal Toxicity
Counsel patients on pregnancy prevention and planning. Advise females of reproductive potential of the potential risk to a fetus and to avoid becoming pregnant while receiving treatment with nintedanib. 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 nintedanib. Advise women taking oral hormonal contraceptives who experience vomiting and/or diarrhea or other conditions where the drug absorption may be reduced to contact their doctor to discuss alternative highly effective contraception. Advise female patients to notify their doctor if they become pregnant or suspect they are pregnant during therapy with nintedanib.

Arterial Thromboembolic Events
Advise patients about the signs and symptoms of acute myocardial ischemia and other arterial thromboembolic events and the urgency to seek immediate medical care for these conditions.

Risk of Bleeding
Bleeding events have been reported. Advise patients to report unusual bleeding.

Gastrointestinal Perforation
Serious gastrointestinal perforation events have been reported. Advise patients to report signs and symptoms of gastrointestinal perforation.

Nephrotic Range Proteinuria
Nephrotic range proteinuria has been reported. Advise patients to report signs and symptoms of proteinuria (e.g., fluid retention, foamy urine).

Lactation
Advise patients that breastfeeding is not recommended while taking nintedanib.

Smokers
Encourage patients to stop smoking prior to treatment with Nintedanib and to avoid smoking when using nintedanib.

Administration
Instruct patients to take nintedanib with food, to swallow nintedanib capsules whole with liquid, and not to chew the capsules due to the bitter taste. Advise patients or caregivers not to open or crush nintedanib capsules and to wash hands immediately and thoroughly if contact with the content of the capsule occurs. Advise patients to not make up for a missed dose.