Pierre Fabre Limited

5.3.      Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

Vinorelbine induced chromosome damages but was not mutagenic in Ames test. It is assumed that vinorelbine can cause mutagenic effects (induction aneuploidy of polyploidy) in man.

In animal reproductive studies, vinorelbine was embryo-feto-lethal and teratogenic.

No haemodynamic effects were found in dogs receiving vinorelbine at maximal tolerated dose; only some minor, non significant disturbances of repolarisation were observed as with other vinca alkaloids tested.

No effect on the cardiovascular system was observed in primates receiving repeated doses of vinorelbine over 39 weeks.

Changes from SPC approved Apr-2011:

4.2.      Posology and method of administration

Administration in children

Safety and efficacy in children have not been established Navelbine is not recommended for use in children due to a lack of data on safety and efficacy. Aand administration is therefore not recommended: see section 5.1.

5.1.      Pharmacodynamic properties

Safety and efficacy of Navelbine in paediatric patients have not been established. Clinical data from a two single-arm studiesy using intravenous vinorelbine in 33 and 46 paediatric patients with recurrent solid tumours, including rhabdomyosarcoma/undiffentiated sarcoma, other soft tissue sarcoma, Ewing sarcoma, liposarcoma, synovial sarcoma, fibrosarcoma, central nervous system cancer, osteosarcoma, neuroblastoma, and CNS tumours, at doses of 30 to 33.75mg/m² D1 and D8 every 3 weeks or once weekly for 6 weeks every 8 weeks showed no meaningful clinical activity. similar to those used in adults, showed no meaningful clinical activity. The  Ttoxicity profile ies wereas similar to thoseat reported in adult patients (: see section 4.2).

Changes made to NAVELBINE® 20 mg soft capsule SmPC dated Apr-2011.

All changes written in blue.

4.2.      Posology and method of administration

Navelbine must be given strictly by the oral route.

Navelbine should be swallowed with water without chewing or sucking the capsule. It is recommended to take the capsule with some food.

A typing error has been corrected in the section for dose modifications:
"...dose reduced from 80 to 60mg/mm³ per week..."  has been corrected to "...dose reduced from 80 to 60mg/m² per week..."

Section 4.3: Contraindications

The following bullet points have been added:

-          Platelet count <  75000/mm³

-          Patients with rare hereditary problems of fructose intolerance should not take this medicine

-          In combination with yellow fever vaccine: see section 4.5

Section 4.4: Special warnings and precautions for use

(Changes in italics)

Navelbine should be prescribed by a physician who is experienced in the use of chemotherapy with facilities for monitoring cytotoxic drugs.

If the patient chews or sucks the capsule by error, the liquid is an irritant. 

In the case of vomiting within a few hours after drug intake, never repeat the administration of this dose. Supportive treatment such as metoclopramide or 5HT₃ antagonists (e.g. ondansetron, granisetron) may reduce the occurrence of this. Navelbine 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.

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.

Special care should be taken when prescribing for patients with:

-    history of ischemic heart disease: see section 4.8

-    poor performance status

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 Navelbine 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.

The following has been taken out: “Because of the presence of Sorbitol, patients with rare hereditary problems of fructose intolerance should not take this medicine.” and moved to section 4.3.

Section 4.8:  Undesirable effects

Whole new section in line with EU guidelines.

The following side effects have been added for Navelbine soft capsules:

Bacterial, viral or fungal infections

Neutropenic sepsis

Leucopenia

Severe hyponatraemia

Insomnia

Headache

Dizziness

Taste disorders

Visual disorders

Hypertension

Hypotension

Cough

Abdominal pain

Dysphagia

Gastro-intestinal bleeding

Dysuria

Other genitourinary disorders

Malaise

Chills

Weight loss and weight gain

Also, the section “Undesirable effects with Navelbine, concentrate for infusion” have been added.

Section 4.2: Posology and method of administration

All references to “Navelbine soft capsules” have been replaced with just “Navelbine”

The sub-headings “In adult patients” and “Dose modification” have been added.

In the second table, “Recommended dose for the next administration” has been replaced with “Recommended dose starting with the next administration”

The sub-heading “In combination therapy” has been replaced with “For combination regimens, the dose and schedule will be adapted to the treatment protocol”

The sentence “Even for patients with BSA 2 m² the total dose should never exceed 160 mg per week.” has been replaced with “Even for patients with BSA ³ 2m² the total dose should never exceed

120 mg per week at 60 mg /m² and 160 mg per week at 80 mg /m²”

The sub-heading “Elderly” has been replaced with “Administration in the elderly”

The sentence “Clinical experience has not identified relevant differences in responses in the elderly or younger patients but greater sensitivity of some older individuals cannot be ruled out.” has been replaced with “Clinical experience has not identified relevant detected any significant differences in responses in the elderly or younger patients among elderly patients with regard to the response rate, although greater sensitivity in some of these patients cannot be excluded. Age does not modify the pharmacokinetics of vinorelbine: see section 5.2.”

The sub-heading “Paediatric patients” has been replaced with “Administration in children” with the following added sentence: “Administration is therefore not recommended”

In addition, the following text has been added:

“Administration in patients with liver insufficiency

Navelbine can be administered at the standard dose of 60 mg/m²/week in patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN). In patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT), Navelbine should be administered at a dose of 50 mg/m²/week. The administration of Navelbine in patients with severe hepatic impairment is contra-indicated: see sections 4.3, 4.4, 5.2.

Administration in patients with renal insufficiency

Given the minor renal excretion, there is no pharmacokinetic justification for reducing the dose of Navelbine in patients with serious renal insufficiency: see sections 4.4, 5.2.

Administration

Navelbine is to be administered orally.
Navelbine must be swallowed whole with water, without chewing, sucking or dissolving the capsule.
It is recommended to administer the capsule with some food.

Specific instructions must be observed for administration of Navelbine :see section 6.6.”

Section 4.4: Special warnings and precautions for use

The following has been deleted:

In patients with impaired liver or kidney function no prospective study is available in order to establish guidelines for the Navelbine soft capsules dose reduction.

However, if there is significant hepatic impairment the dose of Navelbine soft capsules should be reduced. In patients with massive liver metastases (i.e.> 75% of liver volume replaced by the tumour) it is empirically suggested that the dose be reduced by 25 % and the haematological parameters closely monitored.

And replaced with:

Oral Navelbine was studied in patients with liver impairment at the following doses:
- 60 mg/m² in 7 patients with mild liver impairment (bilirubin < 1.5 x ULN, and ALAT and/or ASAT from 1.5 to 2.5 x ULN);

- 50 mg/m² in 6 patients with moderate liver impairment (bilirubin from 1.5 to 3 x ULN, whatever the levels of ALAT and ASAT).

Total clearance of vinorelbine was neither modified between mild and moderate liver impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function. Oral Navelbine was not studied in patients with severe hepatic impairment therefore its use is contra-indicated in these patients: see sections 4.2, 4.3, 5.2.

Section 5.2: Pharmacokinetic properties

The following fragment of a sentence, “…and of 50 mg/m² in patients with moderate liver impairment…” has been replaced with “...and of 50 mg/m² in 6 patients with moderate liver impairment...”

The following text has been added:

“Total clearance of vinorelbine was neither modified between mild and moderate impairment nor was it altered in hepatically impaired patients when compared with clearance in patients with normal liver function.”

Section 4.5:

The following paragraphs have been added:

·         Concomitant use contraindicated

·         Concomitant use not recommended

·         Concomitant use to take into consideration

Section 4.6:

The following changes have been made:

·         The “Pregnancy” paragraph has been rewritten

·         To the “Women of child-bearing potential” paragraph the following has been added: “... and up to 3 months after treatment...”

·         To the “Lactation” paragraph the following has been added:

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

o    “A risk to the suckling child cannot be excluded therefore...”

·         The “Fertility” paragraph has been added

Section 4.7:

The following text has been added:

·         "…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 drug: see section 4.8."

Section 4.9:

The complete section has been reformatted and hepatic disorders added as associated with bone marrow hypoplasia.

Section 5.2:

The following text has been added:

Pharmacokinetic properties

"Pharmacokinetic parameters of vinorelbine were evaluated in blood."

Absorption

“The blood exposure to vinorelbine increases proportionally with the dose up to 100mg/m².”

Distribution

"The steady-state volume of distribution is large, on average 21.2 l/kg (range: 7.5 - 39.7 l/kg), which indicates extensive tissue distribution. Binding to plasma proteins is weak (13.5%), vinorelbine binds strongly to blood cells and especially to platelets (78%)."

“Vinorelbine is not found in the central nervous system.”

Biotransformation

Complete new section

Elimination

Complete new section

Special patients group

Complete new section