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Indications & Uses
Ninacent is indicated for:
Pharmacology
Nintedanib is a small molecule, competitive, triple angiokinase inhibitor. It targets several receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Many of these RTKs are involved in lung fibrosis and tumour angiogenesis, so nintedanib is used to treat proliferative diseases such as idiopathic pulmonary fibrosis, non-small cell lung cancer, and systemic sclerosis-associated interstitial lung disease. The RTKs it inhibits are platelet-derived growth factor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1 to 3, vascular endothelial growth factor receptor (VEGFR), and Fns-Like tyrosine kinase-3 (FLT3). Nintedanib binds to the ATP-binding pocket of these receptors and blocks their activity. That stops the signalling cascades that lead to the proliferation and migration of lung fibroblasts. It also inhibits kinase signalling pathways in various cells within tumour tissues, including endothelial cells, pericytes, smooth muscle cells, and cells contributing to angiogenesis. The end result is inhibition of cell proliferation and apoptosis of the affected tumour cells. Besides blocking RTKs, nintedanib prevents the actions of the nRTKs Lck, Lyn, and Src. It is unclear how much the inhibition of Lck and Lyn adds to the therapeutic efficacy of nintedanib, but inhibition of the Src pathway has been shown to reduce lung fibrosis.
Dosage Reference
Reference Information Only
Dosages shown are general references from official sources. Always consult your doctor or pharmacist for personalized dosing.
Adults:
Treatment with Nintedanib should be started by a physician who has experience in diagnosing and treating IPF.
Posology: The recommended dose is 150 mg Nintedanib twice daily, taken about 12 hours apart. The 100 mg twice daily dose is recommended only for patients who can't tolerate 150 mg twice daily. If a dose is missed, the patient should carry on at the next scheduled time with the recommended dose. No extra dose should be taken to make up for it. The maximum daily dose of 300 mg should not be exceeded.
For NSCLC: The recommended dose of nintedanib is 200 mg twice daily, taken about 12 hours apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle. Nintedanib must not be taken on the same day as docetaxel chemotherapy (day 1). If a dose of nintedanib is missed, the patient should resume at the next scheduled time with the recommended dose. The daily doses should not be increased beyond the recommended dose to make up for missed ones. The maximum daily dose of 400 mg should not be exceeded. Patients may continue nintedanib after docetaxel has been stopped, for as long as clinical benefit is seen or until unacceptable toxicity occurs.
Dose adjustments: Alongside symptomatic treatment where it applies, adverse reactions to Nintedanib may be managed by lowering the dose or by interrupting treatment temporarily until the reaction has settled enough for therapy to continue. Treatment may then be restarted at the full dose (150 mg twice daily) or at a reduced dose (100 mg twice daily). If a patient can't tolerate 100 mg twice daily, Nintedanib should be stopped. When treatment has been interrupted because aspartate aminotransferase (AST) or alanine aminotransferase (ALT) rose above 3x the upper limit of normal (ULN), it can be reintroduced once the transaminases are back to baseline values. It is started at the reduced dose of 100 mg twice daily, and this may later be increased to the full dose of 150 mg twice daily.
Side Effects
Nintedanib has been studied in clinical trials of 1,529 patients with IPF. The safety data below come from two Phase III, randomized, double-blind, placebo-controlled studies (INPULSIS-1 and INPULSIS-2), which included 1,061 patients and compared Nintedanib twice daily with placebo for 52 weeks. Data seen after the medicine reached the market are also included. The adverse reactions reported most often with Nintedanib were diarrhea, nausea and vomiting, abdominal pain, decreased appetite, weight decreased and hepatic enzyme increased. Tabulated list of adverse reactions: a table gives the adverse reactions by MedDRA System Organ Class (SOC) and frequency category. It shows how often each adverse drug reaction (ADR) was reported in the Nintedanib group (638 patients), pooled from the two placebo-controlled Phase III trials of 52 weeks or from the post-marketing period. Frequency categories are defined as follows: 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), and not known (cannot be estimated from the available data).
Cautions & Contraindications
Warnings & Precautions
Diarrhoea In the INPULSIS trials, diarrhoea was the most frequent gastro-intestinal adverse reaction. It was reported in 62.4% of patients treated with Nintedanib and 18.4% of those given placebo. In most patients it was mild to moderate and came within the first 3 months of treatment. Diarrhoea led to dose reduction in 10.7% of patients and to stopping Nintedanib in 4.4% in the clinical trials. After the medicine was marketed, serious cases leading to dehydration and electrolyte disturbances were reported. Patients should be treated at the first signs with adequate hydration and anti-diarrhoeal medicines such as loperamide, and the treatment may need to be interrupted. Nintedanib can then be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). If severe diarrhoea persists despite symptomatic treatment, Nintedanib should be discontinued. Nausea and vomiting Nausea and vomiting were frequently reported gastrointestinal adverse reactions, and in most patients they were mild to moderate. Nausea led to stopping Nintedanib in 2.0% of patients, and vomiting in 0.8%. If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction or treatment interruption may be required. Treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). If severe symptoms persist, Nintedanib should be discontinued. Hepatic function The safety and efficacy of Nintedanib have not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment, so treatment is not recommended in them. Exposure is higher in patients with mild hepatic impairment (Child Pugh A), and the risk of adverse events may be increased. These patients should be treated with a reduced dose of Nintedanib. Drug-induced liver injury has been seen with Nintedanib, including severe liver injury with a fatal outcome. Most hepatic events occur within the first three months of treatment. For this reason, hepatic transaminase and bilirubin levels should be checked before treatment starts and during the first month. After that, patients should be monitored at regular intervals over the next two months and periodically thereafter, for example at each patient visit or as clinically indicated. Elevations of liver enzymes (ALT, AST, ALKP, gamma-glutamyl-transferase (GGT) and bilirubin) were reversible with dose reduction or interruption in most cases. If transaminase (AST or ALT) elevations above 3x ULN are measured, dose reduction or interruption of Nintedanib is recommended and the patient should be monitored closely. Once transaminases are back to baseline values, Nintedanib may be resumed at the full dose (150 mg twice daily) or reintroduced at a reduced dose (100 mg twice daily), which can later be increased to the full dose. If any liver test elevation comes with clinical signs or symptoms of liver injury, such as jaundice, Nintedanib should be permanently discontinued. Other possible causes of the liver enzyme elevations should be investigated. Patients with low body weight (<65 kg), Asian patients and female patients have a higher risk of liver enzyme elevations. Nintedanib exposure rose in a linear way with age, which may also raise the risk of liver enzyme elevations. Close monitoring is recommended in patients with these risk factors. Renal function Renal impairment or failure, in some cases fatal, has been reported with Nintedanib use. Patients should be monitored during therapy, with particular attention to those who have risk factors for renal impairment or failure. If renal impairment or failure occurs, adjusting the therapy should be considered. Haemorrhage Inhibition of vascular endothelial growth factor receptor (VEGFR) might be linked to a higher risk of bleeding. In the INPULSIS trials, bleeding AEs were slightly more frequent in the Nintedanib arm (10.3%) than in the placebo arm (7.8%). Non-serious epistaxis was the most frequent bleeding event. Serious bleeding events were low and similar in the 2 groups (placebo: 1.4%, Nintedanib: 1.3%). Patients at known risk of bleeding, including those with an inherited predisposition to bleeding or those on a full dose of anti-coagulative treatment, were not included in the INPULSIS studies. In the post-marketing period, non-serious and serious bleeding events, some of them fatal, have been reported (in patients with or without anticoagulant therapy or other drugs that could cause bleeding). So these patients should only be treated with Nintedanib if the anticipated benefit outweighs the potential risk. Post-marketing bleeding events include, but are not limited to, those in the gastrointestinal, respiratory and central nervous organ systems, and the gastrointestinal ones were the most frequent. 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 group and 2.5% in the Nintedanib group. Adverse events reflecting ischemic heart disease were balanced between the two groups, but a higher percentage of patients had myocardial infarctions in the Nintedanib group (1.6%) than in the placebo group (0.5%). Caution should be used when treating patients at higher cardiovascular risk, including those with 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 seen in patients treated with Nintedanib. Because of how Nintedanib works, though, patients might have an increased risk of thromboembolic events. Gastrointestinal perforations In the INPULSIS trials, perforation was very rare in both groups: 0% with placebo and 0.3% with Nintedanib (two patients). Because of the mechanism of action of Nintedanib, patients might have an increased risk of gastrointestinal perforation. Cases of gastrointestinal perforation, some of them fatal, have been reported in the post-marketing period. Particular caution should be exercised in patients with previous abdominal surgery, a history of peptic ulceration, diverticular disease, or those receiving corticosteroids or NSAIDs at the same time. Nintedanib should only be started at least 4 weeks after abdominal surgery. It should be permanently discontinued in patients who develop gastrointestinal perforation. Hypertension Nintedanib 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 seen in the INPULSIS trials. Based on its mechanism of action, Nintedanib may impair wound healing. No dedicated studies on the effect of Nintedanib on wound healing were done. So treatment should only be started, or resumed after an interruption around surgery, based on clinical judgement that wound healing is adequate. Co-administration with Pirfenidone A dedicated pharmacokinetic study looked at Nintedanib taken together with Pirfenidone in patients with IPF. The results showed no evidence of a relevant pharmacokinetic drug-drug interaction between the two when given in combination. The number of patients was limited, so the study could only detect the most frequent adverse events. It showed an increase in gastrointestinal adverse events and a trend toward more hepatic adverse events. Since the safety profiles of the two medicines are similar, additive adverse events, including gastrointestinal and hepatic ones, may be expected. The benefit-risk balance of treatment with Pirfenidone at the same time has not been established. Effect on QT interval No evidence of QT prolongation was seen with Nintedanib in the clinical trial programme. Some other tyrosine kinase inhibitors are known to affect QT, so caution should be exercised when giving Nintedanib to patients who may develop QTc prolongation. Allergic reaction Dietary soya products are known to cause allergic reactions, including severe anaphylaxis, in people with soya allergy. Patients with a known allergy to peanut protein have an enhanced risk of severe reactions to soya preparations.
Contraindications
Don't give Nintedanib to anyone who is allergic to it, to peanut or soya, or to any of the excipients.
Pregnancy & Breastfeeding
Women of childbearing potential and contraception
Nintedanib may cause harm to the foetus in humans. Women who could become pregnant should be advised to avoid pregnancy while they are being treated with Nintedanib. They should use adequate contraception during treatment and for at least 3 months after the last dose. No one has studied how Nintedanib affects the metabolism or the efficacy of hormonal contraceptives, so barrier methods should be used as a second form of contraception to avoid pregnancy.
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. Because Nintedanib may harm the foetus in humans too, it must not be used during pregnancy. Female patients should be told to inform their doctor or pharmacist if they become pregnant during therapy. If a patient does become pregnant while taking Nintedanib, she should be told about the possible hazard to the foetus, and stopping the treatment should be considered.
Lactation
There is no information on whether Nintedanib and its metabolites pass into human milk. Pre-clinical studies showed that small amounts of Nintedanib and its metabolites (≤ 0.5% of the administered dose) were secreted into the milk of lactating rats. A risk to newborns and infants cannot be excluded. Breast-feeding should be stopped during treatment with Nintedanib.
Fertility
Pre-clinical investigations found no evidence of impaired male fertility. Subchronic and chronic toxicity studies also found 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.
⚠️ Talk to your doctor before taking any medicine during pregnancy or while breastfeeding.
Use in Special Populations
Elderly patients (≥65 years): No overall differences in safety or efficacy were seen in elderly patients. The dose doesn't need to be adjusted in advance because of age. Patients ≥75 years may be more likely to need a dose reduction to manage adverse effects.
Renal impairment: Less than 1% of a single dose of Nintedanib leaves the body through the kidney. In mild to moderate renal impairment, the starting dose does not need to be adjusted. Safety, efficacy and pharmacokinetics have not been studied in severe renal impairment (<30 ml/min creatinine clearance).
Hepatic impairment: Nintedanib is mostly eliminated through bile and faeces (> 90%). Exposure was higher in patients with hepatic impairment (Child Pugh A, Child Pugh B). In mild hepatic impairment (Child Pugh A), the recommended dose is 100 mg twice daily, approximately 12 hours apart. In these patients, interrupting or stopping treatment should be considered to manage adverse reactions. Safety and efficacy have not been investigated in hepatic impairment classed as Child Pugh B and C. Treating patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment with Nintedanib is not recommended.
Paediatric population: Safety and efficacy in children aged 0 to 18 years have not been established. No data are available.
Storage
Keep Nintedanib in a cool, dry place and away from light. Don't store it above 25°C.
Drug Interactions
Common questions about Ninacent 100 mg
What is Ninacent 100 mg Capsule?
Ninacent 100 mg Capsule is a medicine that contains Nintedanib. It is made by Incepta Pharmaceuticals Ltd. It belongs to the Tyrosine Kinase Inhibitor group of medicines.
What is Ninacent used for?
Ninacent is used for: Cancer.
What are the side effects of Ninacent?
Nintedanib has been studied in clinical trials of 1,529 patients with IPF. The safety data below come from two Phase III, randomized, double-blind, placebo-controlled studies (INPULSIS-1 and INPULSIS-2), which included 1,061 patients and compared Nintedanib twice daily with placebo for 52 weeks.
Can I take Ninacent during pregnancy or while breastfeeding?
Women of childbearing potential and contraception Nintedanib may cause harm to the foetus in humans. Women who could become pregnant should be advised to avoid pregnancy while they are being treated with Nintedanib. Talk to your doctor before taking any medicine during pregnancy or while breastfeeding.
How should I store Ninacent?
Keep Nintedanib in a cool, dry place and away from light. Don't store it above 25°C.
Can I take other medicines with Ninacent?
Some medicines can interact with Nintedanib, for example: Cyclosporine, Erythromycin, Carbamazepine, Rifampicin, Ketoconazole, Phenytoin. Tell your doctor or pharmacist about every medicine you take.
Is there a cheaper medicine with the same ingredient?
Ninacent is already among the lowest-priced brands of Nintedanib at this strength.
Do I need a prescription for Ninacent?
Ninacent is a prescription (Rx) medicine. Take it as your doctor advises.