NAVILIN Capsule Ref.[51234] Active ingredients: Vinorelbine

Special warnings

NAVILIN should be prescribed by a doctor who is experienced in the use of chemotherapy with facilities for monitoring cytotoxic medicines. Blood counts should be taken prior to next dose. Discontinue or reduce the dosage upon evidence of abnormal bone marrow depression.

If the patient chews or sucks the capsule by error, proceed to mouth rinses with water or preferably a normal saline solution.

In the event of the capsule being cut or damaged, the liquid content is an irritant, and so may cause damage if in contact with skin, mucosa or eyes. Damaged capsules should not be swallowed and should be returned to the pharmacy or to the doctor in order to be properly destroyed. If any contact occurs, immediate thorough washing with water or preferably with normal saline solution should be undertaken.

In the case of vomiting within a few hours after medicine intake, do not re-administer. Supportive treatment such as metoclopramide or 5HT₃ antagonists (e.g. ondansetron, granisetron) may reduce the occurrence of this: see section 4.5.

NAVILIN soft capsule is associated with a higher incidence of nausea/vomiting than the intravenous formulation. Primary prophylaxis with antiemetics and administration of the capsules with some food is recommended as this has also been shown to reduce the incidence of nausea and vomiting: see section 4.2.

A low incidence of death (1%) due to neutropenic sepsis has been reported. Bone marrow toxicity, specifically granulocytopenia, is dose-limiting. Complete blood counts with differentials should be performed and results reviewed prior to each dose of

EUROVIN. NAVILIN should not be administered to patients with granulocyte counts <1000 cells/mm³. Patients developing severe granulocytopenia should be monitored carefully for evidence of infection and/ or fever (see section 4.2).

In patients who develop hyperbilirubinemia during treatment with EUROVIN, the dose should be adjusted. Patients receiving concomitant morphine or opioid analgesics: laxatives and careful monitoring of bowel mobility are recommended. Prescription of laxatives may be appropriate in patients with prior history of constipation.

Close haematological monitoring must be undertaken during treatment (determination of haemoglobin level and the leucocyte, neutrophil and platelet counts on the day of each new administration).

Dosing should be determined by haematological status:

• If the neutrophil count is below 1500/mm³ and/or the platelet count is below 100000/mm³, then the treatment should be delayed until recovery.
• For dose escalation from 60 to 80 mg/m² per week, after the third administration: see section 4.2.
• For the administrations given at 80mg/m², if the neutrophil count is below 500/mm³ or more than once between 500 and 1000/mm³, then the treatment should be delayed until recovery.

The administration should not only be delayed but also reduced to 60 mg/m² per week. It is possible to re-escalate the dose from 60 to 80 mg/m² per week: see section 4.2.

Where treatments were initiated at 80 mg/m², a few patients developed excessive neutropenic complications including those with a poor performance status, therefore it is recommended that the starting dose should be 60 mg/m² escalating to 80 mg/m² if the dose is tolerated as described in section 4.2.

If patients present signs or symptoms suggestive of infection, a prompt investigation should be carried out.

Special precautions for use

Special care should be taken when prescribing for patients with:

• history of ischemic heart disease: see section 4.8

NAVILIN should not be given concomitantly with radiotherapy if the treatment field includes the liver.

This product is specifically contra-indicated with yellow fever vaccine and its concomitant use with other live attenuated vaccines is not recommended: see section 4.3. Caution must be exercised when combining NAVILIN and strong inhibitors or inducers of CYP3A4 (see section 4.5), and its combination with phenytoin (like all cytotoxics) and with itraconazole (like all vinca alkaloids) is not recommended.

Total clearance of vinorelbine is neither modified between mild and moderate liver impairment nor is it altered in hepatically impaired patients when compared with clearance in patients with normal liver function. NAVILIN is contra-indicated in patients suffering from severe hepatic impairment: see sections 4.2, 4.3, 5.2.

As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing the dose of NAVILIN in patients with impaired kidney function: see sections 4.2, 5.2.

Excipients

NAVILIN 20 contains 38,44 mg sorbitol per capsule, which is equivalent to 0,10 mg/weight (38,44 mg/383,79 mg).

NAVILIN 30 contains 59,85 mg sorbitol per capsule, which is equivalent to 0,10 mg/weight (59,85 mg/585,94 mg).

The additive effect of concomitantly administered products containing sorbitol and dietary intake of sorbitol should be taken into account. The content of sorbitol in medicines for oral use may affect the bioavailability of other medicines for oral use administered concomitantly.

Due to sorbitol content, patients with rare hereditary problems with fructose intolerance should not take NAVILIN.

NAVILIN 20 contains 8 mg of polysorbate 80 per capsule, which is equivalent to 0,02 mg/weight (8 mg/383,79 mg).

NAVILIN 30 contains 12 mg polysorbate 80 per capsule, which is equivalent to 0,02 mg/weight (12 mg/585,94 mg).

Polysorbate may influence the pharmacokinetics of concomitant medicines (e.g. enhancement of gastrointestinal absorption).

Concomitant use contraindicated

Yellow fever vaccine: as with all cytotoxics, risk of fatal generalised vaccine disease: see section 4.3.

Concomitant use not recommended

Live attenuated vaccines: (for yellow fever vaccine, see concomitant use contraindicated) as with all cytotoxics, risk of generalised vaccine disease, possibly fatal. This risk is increased in patients already immune-depressed by their underlying disease. It is recommended to use an inactivated vaccine when one exists (e.g. poliomyelitis): see section 4.4

Phenytoin: as with all cytotoxics, risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicine or risk of toxicity enhancement or loss of efficacy of the cytotoxic medicine due to increased hepatic metabolism by phenytoin.

Itraconazole: as with all vinca-alkaloids, increased neurotoxicity of vinca-alkaloids due to the decrease of their hepatic metabolism.

Concomitant use to take into consideration

Cisplatin: There is no mutual pharmacokinetic interaction when combining NAVILIN with cisplatin over several cycles of treatment. However, the incidence of granulocytopenia associated with NAVILIN use in combination with cisplatin is higher than associated with NAVILIN single medicine.

Mitomycin C: risk of bronchospasm and dyspnoea are increased, in rare case an interstitial pneumonitis is observed.

Ciclosporin, tacrolimus: excessive immunodepression with risk of lymphoproliferation. As vinca-alkaloids are known as substrates for P-glycoprotein, and in the absence of specific study, caution should be exercised when combining NAVILIN with strong modulators of this membrane transporter.

The combination of NAVILIN with other medicines with known bone marrow toxicity is likely to exacerbate the myelosuppressive adverse effects.

No clinically significant pharmacokinetic interaction is observed when combining vinorelbine with several other chemotherapeutic medicines (paclitaxel, docetaxel, capecitabine and oral cyclophosphamide).

As CYP3A4 is mainly involved in the metabolism of vinorelbine, combination with strong inhibitors of this isoenzyme (e.g. azole antifungals such as ketoconazole and itraconazole) could increase blood concentrations of vinorelbine and combination with strong inducers of this isoenzyme (e.g. rifampicin, phenytoin) could decrease blood concentrations of vinorelbine.

Anti-emetic medicines such as 5HT₃ antagonists (e.g. ondansetron, granisetron) do not modify the pharmacokinetics of NAVILIN soft capsules (see section 4.4).

Anticoagulant treatment: as with all cytotoxics, the frequency of INR (International Normalised Ratio) monitoring should be increased due to the potential interaction with oral anticoagulants and increased variability of coagulation in patients with cancer. Food does not modify the pharmacokinetics of vinorelbine.

Pregnancy

In animal studies vinorelbine was embryo-feto-lethal and teratogenic. NAVILIN should not be used during pregnancy.

Women of child-bearing potential

Women of child-bearing potential must use effective contraception during treatment and up to 3 months after treatment: see section 4.3.

Lactation

It is unknown whether vinorelbine is excreted in human breast milk.

The excretion of vinorelbine in milk has not been studied in animal studies.

A risk to the suckling child cannot be excluded therefore breast feeding must be discontinued before starting treatment with NAVILIN: see section 4.3.

Fertility

Men being treated with NAVILIN are advised not to father a child during and minimally up to 3 months after treatment: see section 4.3.

Prior to treatment advice should be sought for conserving sperm due to the chance of irreversible infertility as a consequence of treatment with vinorelbine.

No studies on the effects on the ability to drive and use machines have been performed, but on the basis of the pharmacodynamic profile, vinorelbine does not affect the ability to drive and use machines. However, caution is necessary in patients treated with vinorelbine considering some adverse effects of the medicine: see section 4.8.

a) Summary of the safety profile

The most frequent reported adverse medicine reactions are bone marrow depression with neutropenia, anaemia and thrombocytopenia, gastrointestinal toxicity with nausea, vomiting, diarrhoea, stomatitis, constipation, fatigue and fever.

NAVILIN soft capsule is used as single medicine or in combination with other chemotherapeutic medicines or targeted therapy medicines such as cisplatin, capecitabine, carboplatin, epirubicin, trastuzumab, erlotinib, sorafenib. The most frequent system organ classes involved are: ‘Blood and lymphatic system disorders’, ‘Gastrointestinal disorders’, ‘Infections and infestations’ and 'General disorders and administration site conditions.

b) Tabulated summary of adverse reactions

The following side effects to be considered in patients treated with NAVILIN:

c) Other special populations

Patients presenting with signs and symptoms suggestive of infection should be promptly investigated and evaluated for the cause. Special care should be taken when prescribing for patients with a history of ischaemic cardiac disease. No prospective study relating altered metabolism of the medicine to its pharmacodynamic effects is available in order to establish liver or kidney function. NAVILIN should not be given concomitantly with radiotherapy if the treatment field includes the liver. As there is a low level of renal excretion there is no pharmacokinetic rationale for reducing NAVILIN dose in patients with impaired kidney function.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8

Not applicable.