Nintedanib Esilate

Registered South African indications:

• Idiopathic pulmonary fibrosis
• Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype
• Systemic sclerosis associated interstitial lung disease (SSc-ILD)

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to peanuts or soya

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to peanuts or soya
• Pregnancy

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl≥30ml/min)
• Hepatic impairment
• Race and body weight
  - Patients weighing <50kg
• Stable brain metastasis
• Active brain metastasis
• Risk factors for thromboembolic events
• Recent history of myocardial infarction
• Stroke
• Idiopathic pulmonary fibrosis (IPF)
• Higher cardiovascular risk including known coronary artery disease
• Risk factors for hypertension
• History of aneurysm
• Previous abdominal surgery
• Recent history of a hollow organ perforation
• Pe-existing gastrointestinal perforation
• May impair ability to drive and operate machinery

South African manufacturer recommendations

• Breastfeeding
• Severe renal impairment (CrCl≥30ml/min)
  - Risk factors for renal impairment or failure
• Hepatic impairment
• Race
  - Asian patients
  - Black patients
• Female patients
• Body weight
  - Low body weight (<65 kg)
• Known risk for bleeding
  - Inherited predisposition to bleeding
• Risk factors for thromboembolic events
• Recent history of myocardial infarction or stroke
• Higher cardiovascular risk including known coronary artery disease
• Risk factors for QTc prolongation
• Pulmonary hypertension
• Risk factors for hypertension
• History of aneurysm
• Previous abdominal surgery
• Wound healing
• Pe-existing gastrointestinal perforation
  - Previous history of peptic ulceration, diverticular disease
• Coadministration with full dose of anticoagulant medicines
• Coadministration with corticosteroids or non-steroidal anti-inflammatory drugs
• May impair ability to drive and operate machinery

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy (Additional agent required)

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Treatment with nintedanib should be initiated and supervised by a physician experienced in the use of anticancer therapies

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Consult specialist for dosages and regimens

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South African manufacturer recommendations

Nintedanib should be initiated by doctors experienced in the management of diseases for which nintedanib is approved

Idiopathic pulmonary fibrosis
Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype
Systemic sclerosis associated interstitial lung disease (SSc-ILD)

• Oral (cap): 150mg, 12hrly; Max: 300mg/24hrs

OR

- For intolerant patients

• Oral (cap): 100mg, 12hrly

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The 100mg, 12hrly dose is only recommended to be used in patients who do not tolerate the 150mg 12hrly dose

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If a dose is missed, the 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

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See additional prescribing points

• Not established for use in children below 18 years

Pregnancy

International manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• There is no information on the use of nintedanib in pregnant women, but preclinical studies in animals have shown reproductive toxicity of this active substance
• As nintedanib may cause foetal harm also in humans, it should not be used during pregnancy unless the clinical condition requires treatment. Pregnancy testing should be conducted at least prior to treatment with nintedanib
• 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, she should be apprised of the potential hazard to the foetus. Termination of the treatment with nintedanib should be considered
• Nintedanib may cause foetal harm in humans. Women of childbearing potential being treated with nintedanib should be advised to avoid becoming pregnant while receiving this treatment and to use adequate contraception during and at least 3 months after the last dose of nintedanib
• Since the effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy

South African manufacturer recommendations

• Contraindicated
• There is no information on the use of nintedanib in pregnant women, but pre-clinical studies in animals have shown reproductive toxicity of this medicine
• 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
• 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

Breastfeeding

• Caution; not recommended
• There is no information on the excretion of nintedanib and its metabolites in human milk
• Preclinical 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 breastfed child cannot be excluded. Breastfeeding should be discontinued during treatment with nintedanib

Fertility

International manufacturer recommendations

• Based on preclinical investigations there is no evidence for impairment of male fertility
• There are no human or animal data on potential effects of nintedanib on female fertility available

South African manufacturer recommendations

• 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 150mg twice daily

Renal Impairment

• Mild to moderate (CrCl≥30ml/min): No dose adjustment recommended
• Severe (CrCl<30ml/min): Caution; no information available 
  The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment 

Hepatic Impairment

International manufacturer recommendations

• Mild (Child-Pugh Class A): Caution; no dose adjustment recommended 
• Moderate to severe (Child-Pugh Classes B & C): Not recommended for use

South African manufacturer recommendations

• Mild (Child-Pugh Class A): Caution; dose adjustment recommended
  Recommended dose: Oral (cap): 100mg, 12hrly
  Treatment interruption or discontinuation for management of adverse reactions should be considered
• Moderate to severe (Child-Pugh Classes B & C): Not recommended for use
  The safety and efficacy of nintedanib have not been investigated in patients with hepatic impairment classified as Child-Pugh B & C

Elderly

International manufacturer recommendations

• No dose adjustment recommended 

South African manufacturer recommendations

• No dose adjustment recommended 
  No overall differences in safety and efficacy were observed for elderly patients. No a-priori dose adjustment is required on the basis of a patient’s age
  Patients ≥75 years may be more likely to require dose reduction to manage adverse effects

Race and body weight

International manufacturer recommendations

• Caution; no dose adjustment recommended
  Based on population pharmacokinetic (PK) analyses, no a priori dose adjustments of nintedanib are necessary
  Safety data for black and African American patients are limited

South African manufacturer recommendations

• Caution; no dose adjustment recommended
  An inverse correlation between body weight and exposure to nintedanib was observed
  The population mean exposure to nintedanib was 33-50 % higher in Chinese, Taiwanese, and Indian patients and 16 % higher in Japanese patients while it was 16-22 % lower in Koreans compared to caucasians (body weight corrected)
  Data from black individuals were very limited but in the same range as for caucasians

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Peripheral neuropathy
• Headache

Cardiovascular Disorders

• Myocardial infarction
• Bleeding
• Venous thromboembolism
• Hypertension
• Aneurysms
• Artery dissections

Gastrointestinal Disorders

• Diarrhoea
• Vomiting
• Nausea
• Abdominal pain
• Perforation
• Pancreatitis
• Colitis

Hepatobiliary Disorders

• Increased alanine aminotransferase (ALT)
• Increased aspartate aminotransferase (AST)
• Increased blood alkaline phosphatase (ALKP)
• Increased gamma-glutamyltransferase (GGT)
• Hyperbilirubinaemia
• Drug-induced liver injury

Genitourinary Disorders

• Proteinuria
• Renal failure

Endocrine and Metabolic Disorders

• Decreased appetite
• Electrolyte imbalance
• Dehydration
• Decreased weight

Skin and Subcutaneous Tissue Disorders

• Mucositis (including stomatitis)
• Rash
• Alopecia
• Pruritus

Immune, Blood and Lymphatic System Disorders

• Febrile neutropenia
• Abscesses
• Sepsis
• Neutropenia (includes febrile neutropenia)
• Thrombocytopenia

• Potent P-gp inhibitors
• Ketoconazole
• Erythromycin
• Potent P-gp inducers
• Rifampicin
• Carbamazepine
• Phenytoin

Other interactions

• St. John's wort

• Hepatic function
• Renal function
• Electrolytes
• Full blood count

Specific cases may require

• Pregnancy status

Additional observations

• Gastrointestinal events (e.g. diarrhoea, nausea, vomiting)
• Arterial thromboembolic events
• Bleeding
• GI perforation
• Prothrombin time (when coadministered with anticoagulants)
• Serious adverse events (when weight <50kg)

Dose adjustments

• In addition to symptomatic treatment if applicable, the management of adverse reactions to nintedanib could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy
• Nintedanib treatment may be resumed at the full dose (150mg, 12hrly) or a reduced dose (100mg, 12hrly)
• If a patient does not tolerate 100mg 12hrly, treatment with nintedanib should be discontinued
• If diarrhoea, nausea and/or vomiting persist despite appropriate supportive care (including antiemetic therapy), dose reduction or treatment interruption may be required
• The treatment may be resumed at a reduced dose (100mg, 12hrly) or at the full dose (150mg, 12hrly)
• In case of persisting severe diarrhoea, nausea and/or vomiting despite symptomatic treatment, therapy with nintedanib 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 nintedanib may be reintroduced at a reduced dose (100mg, 12hrly) which subsequently may be increased to the full dose (150mg, 12hrly)

Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß) and fibroblast growth factor receptors (FGFR 1-3) kinase activity. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling which is crucial for the proliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smooth muscle cells). In addition Fms-like, tyrosine-protein kinase (Flt)-3, lymphocyte-specific tyrosine-protein kinase (Lck) and proto-oncogene tyrosine-protein kinase Src (Src) are inhibited.

Capsule 100mg

• Ofev (Boehringer Ingelheim)
• Sevcad (Boehringer Ingelheim)

Capsule 150mg

• Ofev (Boehringer Ingelheim)
• Sevcad (Boehringer Ingelheim)