Nintedanib 150 Mg/100 mg Capsules

NINTEDANIB CIPLA is indicated in adults for the treatment of Idiopathic Pulmonary Fibrosis (IPF). NINTEDANIB CIPLA is also indicated in adults for the treatment of other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype (see section 5.1). NINTEDANIB CIPLA is indicated in adults for the treatment of systemic sclerosis associated interstitial lung disease (SSc-ILD).

Treatment with NINTEDANIB CIPLA should be initiated by doctors experienced in the management of diseases for which NINTEDANIB CIPLA is approved.

Posology

The recommended dose is 150 mg nintedanib administered 12 hourly. The 100 mg 12 hourly dose is only recommended to be used in patients who do not tolerate the 150 mg 12 hourly 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.

Dose adjustments

In addition to symptomatic treatment if applicable, the management of adverse reactions to NINTEDANIB CIPLA (see sections 4.4 and 4.8) could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. NINTEDANIB CIPLA treatment may be resumed at the full dose (150 mg 12 hourly) or a reduced dose (100 mg 12 hourly). If a patient does not tolerate 100 mg 12 hourly, treatment with NINTEDANIB CIPLA should be discontinued. If diarrhoea, nausea and/or vomiting 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 12 hourly) or at the full dose (150 mg 12 hourly). In case of persisting severe diarrhoea, nausea and/or vomiting despite symptomatic treatment, therapy with NINTEDANIB CIPLA should be discontinued (see section 4.4). 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 NINTEDANIB CIPLA may be reintroduced at a reduced dose (100 mg 12 hourly) which subsequently may be increased to the full dose (150 mg 12 hourly) (see sections 4.4 and 4.8).

Special populations

Elderly patients (u2265 65 years)
No overall differences in safety and efficacy were observed for elderly patients. No a-priori dose adjustment is required on the basis of a patientu2019s age. Patients u2265 75 years may be more likely to require dose reduction to manage adverse effects (see section 5.2).

Renal impairment
Less than 1 % of a single dose of nintedanib is excreted via the kidney (see section 5.2). Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (< 30 mL/min creatinine clearance).

Hepatic impairment
Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90 %). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B; see section 5.2). In patients with mild hepatic impairment (Child Pugh A), the recommended dose of NINTEDANIB CIPLA is 100 mg 12 hourly. In patients with mild hepatic impairment (Child Pugh A), treatment interruption or discontinuation for management of adverse reactions should be considered. The safety and efficacy of nintedanib have not been investigated in patients with hepatic impairment classified as Child Pugh B and C. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with NINTEDANIB CIPLA is not recommended (see section 5.2).

Paediatric population
The safety and efficacy of NINTEDANIB CIPLA in children aged 0 to 18 years have not been established. No data are available.

Method of administration
NINTEDANIB CIPLA is for oral use. The capsules should be taken with food, swallowed whole with water, and should not be chewed. The capsule should not be opened or crushed (see section 6.6).

• Hypersensitivity to nintedanib, to peanuts or soya, or to any of the excipients listed in section 6.1.
• Pregnancy (see section 4.6).

Gastrointestinal disorders

Diarrhoea
Diarrhoea is the frequent gastrointestinal adverse reaction reported (see section 4.8). In most patients the adverse reaction can be mild to moderate intensity and occur within the first 3 months of treatment. Diarrhoea led to dose reduction in patients and to discontinuation of nintedanib in patients in clinical trials. Serious cases of diarrhoea leading to dehydration and electrolyte disturbances have been reported in the post-marketing period. Patients should be treated at first signs with adequate hydration and anti-diarrhoeal medicines, e.g., loperamide. Treatment interruption should be considered if diarrhoea and dehydration do not improve. NINTEDANIB CIPLA treatment may be resumed at a reduced dose (100 mg 12 hourly) or at the full dose (150 mg 12 hourly). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with NINTEDANIB CIPLA should be discontinued.

Nausea and vomiting
Nausea and vomiting can be frequent gastrointestinal adverse reactions (see section 4.8). In most patients with nausea and vomiting, the event was of mild to moderate intensity. In clinical trials nausea and vomiting led to discontinuation of nintedanib as in NINTEDANIB CIPLA in 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 12 hourly) or at the full dose (150 mg 12 hourly). In case of persisting severe symptoms therapy with NINTEDANIB CIPLA should be discontinued.

Hepatic function
The safety and efficacy of nintedanib as in NINTEDANIB CIPLA has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore, treatment with NINTEDANIB CIPLA is not recommended in such patients (see section 4.2). 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 NINTEDANIB CIPLA (see sections 4.2 and 5.2).

Cases of drug-induced liver injury have been observed with NINTEDANIB CIPLA 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 CIPLA. 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 (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl-transferase (GGT), see section 4.8) and bilirubin can be 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 NINTEDANIB CIPLA is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with NINTEDANIB CIPLA may be resumed at the full dose (150 mg 12 hourly) or reintroduced at a reduced dose (100 mg 12 hourly) which subsequently may be increased to the full dose (see section 4.2). If any liver test elevations are associated with clinical signs or symptoms of liver injury, e.g., jaundice, treatment with NINTEDANIB CIPLA 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. Nintedanib as in NINTEDANIB CIPLA exposure increased linearly with patient age, which may also result in a higher risk of developing liver enzyme elevations (see section 5.2). 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 CIPLA use (see section 4.8). Patients should be monitored during NINTEDANIB CIPLA 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 (see section 4.2 Dose adjustments).

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 anticoagulant medicines were not included in the 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 medicines that could cause bleeding). Therefore, these patients should only be treated with NINTEDANIB CIPLA if the anticipated benefit outweighs the potential risk.

Arterial thromboembolic events
Patients with a recent history of myocardial infarction or stroke were excluded from the clinical trials. In the clinical trials, arterial thromboembolic events were infrequently reported. In a clinical trial, a higher percentage of patients experienced myocardial infarctions in the nintedanib group compared to the placebo group, while adverse events reflecting ischaemic heart disease were balanced between the nintedanib as in NINTEDANIB CIPLA and placebo groups. In a clinical trial, myocardial infarction was observed with low frequency: nintedanib as in NINTEDANIB CIPLA versus placebo. In a clinical trial, myocardial infarction was observed with low frequency in the placebo group and not observed in the nintedanib group. Regular cardiac monitoring (e.g., ECG, echocardiography) 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 ischaemia.

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 CIPLA, 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 as in NINTEDANIB CIPLA treated patients. Due to the mechanism of action of NINTEDANIB CIPLA patients might have an increased risk of thromboembolic events.

Gastrointestinal perforations and ischaemic colitis
In the clinical trials, the frequency of patients with gastrointestinal perforation was up in both treatment groups. Due to the mechanism of action of NINTEDANIB CIPLA 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 Non-Steroidal Anti-inflammatory drugs (NSAIDs). NINTEDANIB CIPLA should only be initiated at least 4 weeks after abdominal surgery. Therapy with NINTEDANIB CIPLA should be permanently discontinued in patients who develop gastrointestinal perforation or ischaemic colitis. Exceptionally, NINTEDANIB CIPLA can be reintroduced after complete resolution of ischaemic colitis and careful assessment of the patientu2019s 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 as in NINTEDANIB CIPLA 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 as in NINTEDANIB CIPLA. If laboratory or clinical findings associated with TMA occur in a patient receiving nintedanib as in NINTEDANIB CIPLA, treatment with nintedanib as in NINTEDANIB CIPLA should be discontinued and thorough evaluation for TMA should be completed.

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

Pulmonary hypertension
Data on the use of nintedanib as in NINTEDANIB CIPLA in patients with pulmonary hypertension is limited. Patients with significant pulmonary hypertension (cardiac index u2264 2 L/min/mu00b2, or parenteral epoprostenol / treprostinil, or significant right heart failure) were excluded from the INBUILD and SENSCIS trials. NINTEDANIB CIPLA 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. Based on the mechanism of action NINTEDANIB CIPLA may impair wound healing. No dedicated studies investigating the effect of nintedanib as in NINTEDANIB CIPLA on wound healing were performed. Treatment with NINTEDANIB CIPLA 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 as in NINTEDANIB CIPLA 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 CIPLA and pirfenidone when administered in combination (see section 5.2). Given the similarity in safety profiles for both medicines, 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 nintedanib as in NINTEDANIB CIPLA (see section 5.1). As some other tyrosine kinase inhibitors are known to exert an effect on QT, caution should be exercised when administering NINTEDANIB CIPLA 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.

P-glycoprotein (P-gp)
Nintedanib as in NINTEDANIB CIPLA is a substrate of P-gp (see section 5.2). 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 C max in a dedicated drug-drug interaction study. In a drug-drug interaction study with the potent P-gp inducer rifampicin, exposure to nintedanib as in NINTEDANIB CIPLA decreased to 50,3 % based on AUC and to 60,3 % based on C max upon co-administration with rifampicin compared to administration of nintedanib as in NINTEDANIB CIPLA alone. If co-administered with NINTEDANIB CIPLA, potent P-gp inhibitors (e.g., ketoconazole, erythromycin or ciclosporin) may increase exposure to nintedanib as in NINTEDANIB CIPLA. In such cases, patients should be monitored closely for tolerability of nintedanib as in NINTEDANIB CIPLA. Management of side effects may require interruption, dose reduction, or discontinuation of therapy with NINTEDANIB CIPLA (see section 4.2).

Potent P-gp inducers (e.g., rifampicin, carbamazepine, phenytoin, and St. Johnu2019s wort) may decrease exposure to nintedanib as in NINTEDANIB CIPLA. Selection of an alternate concomitant medicine with no or minimal P-gp induction potential should be considered.

Cytochrome (CYP) -enzymes
Only a minor extent of the biotransformation of nintedanib as in NINTEDANIB CIPLA consisted of CYP pathways. Nintedanib as in NINTEDANIB CIPLA and its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes (see section 5.2). The likelihood of drug-drug interactions with NINTEDANIB CIPLA based on CYP metabolism is therefore considered to be low.

Co-administration with other medicines
Co-administration of nintedanib as in NINTEDANIB CIPLA with oral hormonal contraceptives did not alter the pharmacokinetics of oral hormonal contraceptives to a relevant extent (see section 5.2). Co-administration of nintedanib as in NINTEDANIB CIPLA with bosentan did not alter the pharmacokinetics of nintedanib as in NINTEDANIB CIPLA (see section 5.2).

Women of childbearing potential / Contraception in males and females
Nintedanib as in NINTEDANIB CIPLA may cause foetal harm in humans. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with NINTEDANIB CIPLA and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of NINTEDANIB CIPLA. Nintedanib as in NINTEDANIB CIPLA does not relevantly affect the plasma exposure of ethinylestradiol and levonorgestrel (see section 5.2). 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 CIPLA in pregnant women. As nintedanib as in NINTEDANIB CIPLA may cause foetal harm also in humans, it must not be used during pregnancy (see section 4.3) and pregnancy testing must be conducted prior to treatment with NINTEDANIB CIPLA and during treatment as appropriate. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy with NINTEDANIB CIPLA. If the patient becomes pregnant while receiving NINTEDANIB CIPLA, treatment must be discontinued, and she should be apprised of the potential hazard to the foetus.

Breastfeeding
There is no information on the excretion of nintedanib as in NINTEDANIB CIPLA and its metabolites in human milk. Pre-clinical studies showed that small amounts of nintedanib as in NINTEDANIB CIPLA and its metabolites (u2264 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 CIPLA.

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.

The undesirable effects (see section 4.8) of NINTEDANIB CIPLA may impair the ability to drive and use machines. NINTEDANIB CIPLA 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 CIPLA.

a) Summary of the safety profile
In clinical studies and during the post-marketing experience, the frequently reported adverse reactions associated with the use of nintedanib as in NINTEDANIB CIPLA included diarrhoea, nausea and vomiting, abdominal pain, decreased appetite, decreased weight and increased hepatic enzymes. For the management of selected adverse reactions please also refer to section 4.4.

b) Tabulated summary of adverse reactions
The following adverse reactions have been classified according to the following categories, frequent, less frequent and frequency unknown.

Frequency

MedDRA system organ Class

Idiopathic pulmonary fibrosis

Other chronic fibrosing ILDs with a progressive phenotype

Systemic sclerosis associated interstitial lung disease

Blood and lymphatic system disorders

Thrombocytopenia

Less frequent

Less frequent

Less frequent

Metabolism and nutrition disorders

Decreased weight

Frequent

Frequent

Frequent

Decreased appetite

Frequent

Frequent

Frequent

Dehydration

Less frequent

Less frequent

Frequency unknown

Cardiac disorders

Myocardial infarction

Less frequent

Less frequent

Frequency unknown

Vascular disorders

Bleeding (see section 4.4)

Frequent

Frequent

Frequent

Hypertension

Less frequent

Frequent

Frequent

Aneurysms and artery dissections

Frequency unknown

Frequency unknown

Frequency unknown

Gastrointestinal disorder

Diarrhoea

Frequent

Frequent

Frequent

Nausea

Frequent

Frequent

Frequent

Abdominal pain

Frequent

Frequent

Frequent

Vomiting

Frequent

Frequent

Frequent

Pancreatitis

Less frequent

Less frequent

Frequency unknown

Colitis

Less frequent

Less frequent

Less frequent

Hepatobiliary disorders

Drug induced liver injury

Less frequent

Frequent

Less frequent

Increased hepatic enzyme

Frequent

Frequent

Frequent

Increased alanine aminotransferase (ALT)

Frequent

Frequent

Frequent

Increased aspartate aminotransferase (AST)

Frequent

Frequent

Frequent

Increased gamma glutamyl transferase (GGT)

Frequent

Frequent

Frequent

Hyperbilirubinemia

Less frequent

Less frequent

Frequency unknown

Increased blood alkaline phosphatase (ALP)

Less frequent

Frequent

Frequent

Skin and subcutaneous tissue disorders

Rash

Frequent

Frequent

Less frequent

Pruritus

Less frequent

Less frequent

Less frequent

Alopecia

Less frequent

Less frequent

Frequency unknown

Renal and urinary disorders

Renal failure (see section 4.4)

Frequency unknown

Less frequent

Less frequent

Proteinuria

Less frequent

Less frequent

Frequency unknown

Nervous system disorders

Headache

Frequent

Frequent

Frequent

Description of selected adverse reactions

Diarrhoea
In clinical trials, diarrhoea was the most frequent gastrointestinal event reported. In most patients, the event was of mild to moderate intensity. More than two thirds of patients experiencing diarrhoea reported its first onset already during the first three months of treatment. In most patients, the events were managed by anti-diarrhoeal therapy, dose reduction or treatment interruption (see section 4.4).

Increased hepatic enzymes
In the clinical trials, liver enzyme elevations (see section 4.4) were reported in patients treated with nintedanib as in NINTEDANIB CIPLA and placebo, respectively. In a clinical trial, liver enzyme elevations were reported in patients treated with nintedanib as in NINTEDANIB CIPLA and placebo, respectively. In a clinical trial, liver enzyme elevations were reported in patients treated with nintedanib as in NINTEDANIB CIPLA and placebo, respectively. Elevations of liver enzymes were reversible and not associated with clinically manifest liver disease.

For further information about special populations, recommended measures and dosing adjustments in case of diarrhoea and hepatic enzyme increases, refer additionally to sections 4.4 and 4.2, respectively.

Bleeding
In clinical trials, the frequency of patients who experienced bleeding was slightly higher in patients treated with nintedanib as in NINTEDANIB CIPLA or comparable between the treatment arms. Non-serious epistaxis was the most frequent bleeding event reported. Serious bleeding events occurred with low frequencies in the 2 treatment groups. Post-marketing bleeding events include but are not limited to gastrointestinal, respiratory and central nervous organ systems, with the most frequent being gastrointestinal (see section 4.4).

Proteinuria
In clinical trials, the frequency of patients who experienced proteinuria was low and comparable between the treatment arms. Nephrotic syndrome has not been reported in clinical trials. 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 as in NINTEDANIB CIPLA was discontinued, with residual proteinuria in some cases. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome (see section 4.4).

There is no specific antidote or treatment for NINTEDANIB CIPLA 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 as in NINTEDANIB CIPLA, i.e., increased liver enzymes and gastrointestinal symptoms. Both patients recovered from these adverse reactions. In the INPULSIS trials, one patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A non-serious adverse event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events. In case of overdose, treatment should be interrupted, and general supportive measures initiated as appropriate.