Last Updated on eMC 13-06-2017 View medicine  | Roche Products Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:02-06-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike-through deleted:

4.1          Therapeutic indications

[…]

Bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. (See section 5.1).

Bevacizumab, in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel, is indicated for treatment of adult patients with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents.

[…]

4.2          Posology and method of administration

[…]

Treatment of platinum-sensitive recurrent disease: Avastin is administered in combination with either carboplatin and gemcitabine for 6 cycles and up to 10 cycles or in combination with carboplatin and paclitaxel for 6 cycles and up to 8 cycles, followed by continued use of Avastin as single agent until disease progression.The recommended dose of Avastin is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.

[…]

4.8          Undesirable effects

Summary of the safety profile

The overall safety profile of Avastin is based on data from over 5,7400 patients with various malignancies, predominantly treated with Avastin in combination with chemotherapy in clinical trials.

[…]

Table 1: Adverse Reactions by Frequency

System organ class

Very Common

Common

Uncommon

Rare

Very Rare

Frequency Not Known

Metabolism and nutrition disorders

Anorexia

Hypomagnesaemia

Hyponatraemia

 

Dehydration

 

 

 

 

Respiratory, thoracic and mediastinal disorders

Dyspnoea,

Rhinitis

Epistaxis

Cough

Pulmonary

haemorrhage/

Haemoptysisb,d,

Pulmonary

embolism,

Epistaxis,

Hypoxia,

Dysphoniaa

 

 

 

Pulmonary

hypertensiona,

Nasal septum

perforationa

Musculoskeletal  and connective tissue disorders

Arthralgia

Myalgia

 

Fistulab,d,

Myalgia,

Muscular weakness,

Back pain

 

 

 

Osteonecrosis of the jawa,b

Non-mandibular osteonecrosisa,f

 

[…]

Table 2: Severe Adverse Reactions by Frequency

System organ class

Very Common

Common

Uncommon

Rare

Very Rare

Frequency Not Known

Metabolism and nutrition disorders

 

Dehydration

Hyponatraemia

 

 

 

 

 

[…]

Description of selected serious adverse reactions

 

Gastrointestinal (GI) perforations and Fistulae (see section 4.4)

Avastin has been associated with serious cases of gastrointestinal perforation.

Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% in patients with non-squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breast cancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer receiving front-line treatment, and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), GI perforations (all grade) were reported in 3.2% of patients, all of whom had a history of prior pelvic radiation.

[…]

GI-vaginal Fistulae in study GOG-0240

In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal fistulae was 8.3% in Avastin‑treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with Avastin + chemotherapy was higher in patients with recurrence within the field of prior radiation (16.7%) compared with patients with no prior radiation and/ or no recurrence inside the field of prior radiation (3.6%). with recurrence outside the field of prior radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies.

[…]

In clinical trials of ovarian cancer, Grade 3-5 wound healing complications were observed in up to 1.82% of patients in the bevacizumab arm versus 0.1% in the control arm (NCI-CTCAE v.3).

[…]

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was reported in up to 8.110.9% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. Testing for proteinuria is recommended prior to start of Avastin therapy. In most clinical trials urine protein levels of ³ 2g/24 hrs led to the holding of Avastin until recovery to < 2g/24 hrs.

[…]

5.1          Pharmacodynamic properties

[…]

GOG-0218

The GOG-0218 study was a phase III multicentre, randomised, double-blind, placebo-controlled, three arm study evaluating the effect of adding Avastin to an approved chemotherapy regimen (carboplatin and paclitaxel) in patients with advanced (FIGO Sstages IIIB, IIIC and IV according to FIGO staging version dated 1988) epithelial ovarian, fallopian tube or primary peritoneal cancer.

[…]

BO17707 (ICON7)

BO17707 was a Phase III, two arm, multicentre, randomised, controlled, open-label study comparing the effect of adding Avastin to carboplatin plus paclitaxel in patients with FIGO stage I or IIA (Grade 3 or clear cell histology only; n = 142), or FIGO stage IIB - IV (all Grades and all histological types, n = 1386) epithelial ovarian, fallopian tube or primary peritoneal cancer following surgery (NCI-CTCAE v.3). FIGO staging version dated 1988 was used in this trial.

[…]

Recurrent ovarian cancer

The safety and efficacy of Avastin in the treatment of recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer was studied in threetwo phase III trials (AVF4095g ,and MO22224 and GOG-0213) with different patient populations and chemotherapy regimens.

          AVF4095g evaluated the efficacy and safety of bevacizumab in combination with carboplatin and gemcitabine, followed by bevacizumab as a single agent in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

          GOG-0213 evaluated the efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel, followed by bevacizumab as a single agent in patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

          MO22224 evaluated the efficacy and safety of bevacizumab in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

[…]

GOG-0213

GOG-0213, a phase III randomized controlled open label trial, studied the safety and efficacy of Avastin in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting. There was no exclusion criterion for prior anti-angiogenic therapy. The study evaluated the effect of adding Avastin to carboplatin+paclitaxel and continuing Avastin as a single agent until disease progression or unacceptable toxicity compared to carboplatin+paclitaxel alone.

 

A total of 673 patients were randomized in equal proportions to the following two treatment arms:

     CP arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) every 3 weeks for 6 and up to 8 cycles.

     CPB arm: Carboplatin (AUC5) and paclitaxel (175 mg/m2 IV) and concurrent Avastin (15 mg/kg) every 3 weeks for 6 and up to 8 cycles, followed by Avastin (15 mg/kg every 3 weeks) alone until disease progression or unacceptable toxicity.

Most patients in both the CP arm (80.4%) and the CPB arm (78.9%) were White. The median age was 60.0 years in the CP arm and 59.0 years in the CPB arm. The majority of patients (CP: 64.6%; CPB: 68.8%) were in the age category < 65 years. At baseline, most patients in both treatment arms had a GOG PS of 0 (CP: 82.4%: CPB; 80.7%) or 1 (CP: 16.7%: CPB; 18.1%). A GOG PS of 2 at baseline was reported in 0.9% of patients in the CP arm and in 1.2% of patients in the CPB arm.“

The primary efficacy endpoint was overall survival (OS). The main secondary efficacy endpoint was progression-free survival (PFS).Results are presented in Table 22.

 

Table 22               Efficacy results1,2 from study GOG-0213

Primary Endpoint

Overall Survival (OS)

CP

(n=336)

CPB

(n=337)

Median OS (months)

37.3

42.6

Hazard ratio (95% CI) (eCRF)a

0.823 [CI: 0.680, 0.996]

p-Value

0.0447

Hazard ratio (95% CI) (registration form)b

0.838 [CI: 0.693, 1.014]

p-Value

0.0683

Secondary Endpoints

Progression-free survival (PFS)

CP

(n=336)

CPB

(n=337)

Median PFS (months)

10.2

13.8

Hazard ratio (95% CI)

0.613 [CI: 0.521, 0.721]

p-value

<0.0001

1 Final Analysis 2 Tumour assessments and response evaluations were determined by the investigators using the GOG RECIST criteria (Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228Y247).

 

a Hazard ratio was estimated from Cox proportional hazards models stratified by the duration of platinum free-interval prior to enrolling onto this study per eCRF (electronic case report form) and secondary surgical debulking status Yes/No (Yes=randomized to undergo cytoreduction or randomized to not undergo cytoreduction; No= not a candidate or did not consent to cytoreduction). b stratified by the duration of treatment free-interval prior to enrolling onto this study per the registration form, and secondary surgical debulking status Yes/No.

 

The trial met its primary objective of OS improvement. Treatment with Avastin at 15 mg/kg every 3 weeks in combination with chemotherapy (carboplatin and paclitaxel) for 6 and up to 8 cycles, followed by Avastin until disease progression or unacceptable toxicity resulted, when data were derived from eCRF, in a clinically meaningful and statistically significant improvement in OS compared to treatment with carboplatin and paclitaxel alone.

[…]

10.          DATE OF REVISION OF THE TEXT

02 June 2017

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:26-01-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike-through deleted:

 

4.2          Posology and method of administration

[…]

Paediatric population

 

The safety and efficacy of bevacizumab in children less than 18 years old have not been established. Avastin is not approved for use in patients under the age of 18 years. Currently available data are described in sections 4.8, 5.1 and 5.2 butThere is no relevant use of bevacizumab in the paediatric population and no recommendation on a posology can be made. Currently available data are described in sections 4.8, 5.1, 5.2 and 5.3.

 

There is no relevant use of bevacizumab in the paediatric population in the indications for treatment of cancers of the colon, rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney.

[…]

 

4.8          Undesirable effects

[…]

Paediatric population

The safety and efficacy of Avastin in children less than 18 years old  have not been established.

 

In study BO25041 of Avastin added to postoperative radiation therapy (RT) with concomitant and adjuvant temozolomide in paediatric patients with newly diagnosed supratentorial, infratentorial, cerebellar, or peduncular high-grade glioma, the safety profile was comparable with that observed in other tumour types in adults treated with Avastin. 

 

In study BO20924 of Avastin with current standard of care in rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma, the safety profile of Avastin treated children was comparable with that observed in adults treated with Avastin.

 

Avastin is not approved for use in patients under the age of 18 years. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years treated with Avastin (please see section 5.3).

[…]

 

5.1          Pharmacodynamic properties

[…]

High-grade glioma

Anti-tumour activity was not observed in two earlier studies among a total of 30 children aged > 3 years old with relapsed or progressive high-grade glioma when treated with bevacizumab and irinotecan (CPT-11). There is insufficient information to determine the safety and efficacy of bevacizumab in children with newly-diagnosed high-grade glioma.

 

·              In a single-arm study (PBTC-022), 18 children with recurrent or progressive non-pontine high-grade glioma (including 8 with glioblastoma [WHO Grade IV], 9 with anaplastic astrocytoma [Grade III] and 1 with anaplastic oligodendroglioma [Grade III]) were treated with bevacizumab (10 mg/kg) two weeks apart and then with bevacizumab in combination with CPT-11 (125-350 mg/m²) once every two weeks until progression. There were no objective (partial or complete) radiological responses (MacDonald criteria). Toxicity and adverse reactions included arterial hypertension and fatigue as well as CNS ischaemia with acute neurological deficit. 

 

·      In a retrospective single institution series, 12 consecutive (2005 to 2008) children with relapsed or progressive high-grade glioma (3 with WHO Grade IV, 9 with Grade III) were treated with bevacizumab (10 mg/kg) and irinotecan (125 mg/m²) every 2 weeks. There were no complete responses and 2 partial responses (MacDonald criteria).

 

In a randomized phase II study (BO25041) a total of 121 patients aged ≥ 3 years to <18 years with newly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG) were treated with post operative radiation therapy (RT) and adjuvant temozolomide (T) with and without bevacizumab: 10 mg/kg every 2 weeks IV.  

 

The study did not meet its primary endpoint of demonstrating a significant improvement of EFS (Central Radiology Review Committee (CRRC)-assessed) when bevacizumab was added to the RT/T arm compared with RT/T alone (HR = 1.44; 95% CI: 0.90, 2.30). These results were consistent with those from various sensitivity analyses and in clinically relevant subgroups. The results for all secondary endpoints (investigator assessed EFS, and ORR and OS) were consistent in showing no improvement associated with the addition of bevacizumab to the RT/T arm compared with the RT/T arm alone.

 

Addition of Avastin to RT/T did not demonstrate clinical benefit in study BO25041 in 60 evaluable children patients with newly diagnosed supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG) (See section 4.2 for information on paediatric use).

 

Soft tissue sarcoma

In a randomized phase II study (BO20924) a total of 154 patients aged ≥ 6 months to <18 years with newly diagnosed metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma were treated with standard of care (Induction IVADO/IVA+/- local therapy followed by Maintenance Vinorelbine and cyclophosphamide) with or without bevacizumab (2.5 mg/kg/week) for a total duration of treatment of approximately 18 months. At the time of the final primary analysis, the primary endpoint of EFS by independent central review did not show a statistically significant difference between the two treatment arms, with HR of 0.93 (95% CI: 0.61, 1.41; p-value = 0.72).  The difference in ORR per independent central review was 18% (CI: 0.6%, 35.3%) between the two treatment arms in the few patients who had evaluable tumor at baseline and had a confirmed response prior to receiving any local therapy : 27/75 patients (36.0%, 95% CI: 25.2%, 47.9%) in the Chemo arm and 34/63 patients (54.0%, 95% CI: 40.9%, 66.6%) in the Bv + Chemo arm. The secondary endpoint of Overall Survival (OS) was not mature . Until mature OS results and safety data are available no definitive conclusion can be drawn on the benefit/risk balance.

[…]

 

5.2          Pharmacokinetic properties

[…]

Pharmacokinetics in special populations

The population pharmacokinetics were analysed in adult and pediatric patients to evaluate the effects of demographic characteristics. In adults, tThe results showed no significant difference in the pharmacokinetics of bevacizumab in relation to age.

 

Renal impairment

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in renally impaired patients since the kidneys are not a major organ for bevacizumab metabolism or excretion.

 

Hepatic impairment

No trials have been conducted to investigate the pharmacokinetics of bevacizumab in patients with hepatic impairment since the liver is not a major organ for bevacizumab metabolism or excretion.

 

Paediatric population

The pharmacokinetics of bevacizumab were evaluated in 152 paediatric patientschildren, adolescents and young adults (7 months to 21 years, 5.9 to 125 kg) across 4 clinical studies in paediatrics using a population pharmacokinetic model. The pharmacokinetic results show that the clearance and volume of distribution of bevacizumab were comparable  between paediatric and young adult patients when normaliszed by body weight, with exposure trending lower as body weight decreased. Age was not associated with the pharmacokinetics of bevacizumab when body weight was taken into account.

 

In Study BO20924, the pharmacokinetics of bevacizumab was well characterized by the pediatric population PK model in 70 paediatric patients (1.4 to 17.6 years; 11.6 to 77.5 kg). Based on population PK model simulations, bevacizumab exposure was generally lower in paediatric patients from Study BO20924 as compared to a typical adult patient  at the same dose, and trended lower as body weight decreased.

 

The pharmacokinetics of bevacizumab was well characterized by the paediatric population PK model for 70 patients in Study BO20924 ((1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in Study BO25041 (1 to 17 years; 11.2 to 82.3 kg). In Study BO20924, bevacizumab exposure was generally lower compared to a typical adult patient at the same dose. In Study BO25041, bevacizumab exposure was similar compared to a typical adult at the same dose. In both studies, bevacizumb exposure trended lower as body weight decreased.

10.          DATE OF REVISION OF THE TEXT

 

26 January 2017

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:15-09-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike-through deleted:


4.2          Posology and method of administration

[…]

Paediatric population

 

The safety and efficacy of bevacizumab in children less than 18 years old and adolescents have not been established. Avastin is not approved for use in patients under the age of 18 years. There is no relevant use of bevacizumab in the paediatric population in the granted indicationsand no recommendation on a posology can be made. Currently available data are described in sections 4.8, 5.1, 5.2 and 5.3 but no recommendation on a posology can be made.

 

Addition of Avastin to standard of care did not demonstrate clinical benefit in clinical trial BO20924, in 71 evaluable children (from age 6 months to less than 18 years old) patients with metastatic Rhabdomyosarcoma and non-Rhabdomyosarcoma Soft Tissue Sarcoma or in paediatric patients with primary CNS tumors.

 

 

Avastin should not be used in children aged 3 years to less than 18 years with recurrent or progressive high-grade glioma because of efficacy concerns (see section 5.1 for results of paediatric trials).

 

Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended as described in section 4.4.

 

 

Method of administration

 

The initial dose should be delivered over 90 minutes as an intravenous infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.

 

It should not be administered as an intravenous push or bolus.

 

Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be permanently discontinued or temporarily suspended as described in section 4.4.

[…]


4.8          Undesirable effects

[…]

Paediatric population

The safety and efficacy of Avastin in children less than 18 years old  have and adolescents has not been established.

 

In study BO20924 of Avastin with current standard of care in metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma, the safety profile of Avastin treated children was comparable with that observed in adults treated with Avastin.

 

[…]


5.1          Pharmacodynamic properties

[…]

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies, in all subsets of the paediatric population, in breast carcinoma, adenocarcinoma of the colon and rectum, lung carcinoma (small cell and non-small cell carcinoma), kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney), ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumours), fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) and cervix and corpus uteri carcinoma.

 

Anti-tumour activity was not observed in two studies among a total of 30 children aged > 3 years old with relapsed or progressive high-grade glioma when treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of bevacizumab in children with newly-diagnosed high-grade glioma.

 

In a single-arm study (PBTC-022), 18 children with recurrent or progressive non-pontine high-grade glioma (including 8 with glioblastoma [WHO Grade IV], 9 with anaplastic astrocytoma [Grade III] and 1 with anaplastic oligodendroglioma [Grade III]) were treated with bevacizumab (10 mg/kg) two weeks apart and then with bevacizumab in combination with CPT-11 (125-350 mg/m²) once every two weeks until progression. There were no objective (partial or complete) radiological responses (MacDonald criteria). Toxicity and adverse reactions included arterial hypertension and fatigue as well as CNS ischaemia with acute neurological deficit. 

 

·      In a retrospective single institution series, 12 consecutive (2005 to 2008) children with relapsed or progressive high-grade glioma (3 with WHO Grade IV, 9 with Grade III) were treated with bevacizumab (10 mg/kg) and irinotecan (125 mg/m²) every 2 weeks. There were no complete responses and 2 partial responses (MacDonald criteria).

 

Anti-tumour activity was not observed Iin a randomized phase II study (BO20924) among a total of 154 patients aged ≥ 6 months to <18 years with newly diagnosed metastatic rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma . In this study, children were treated with standard of care (Induction IVADO/IVA+/- local therapy followed by Maintenance Vinorelbine and cyclophosphamide) with or without bevacizumab (2.5 mg/kg/week) for a total duration of treatment of approximately 18 months. At the time of the final primary analysis, the primary endpoint of EFS by independent central review did not show a statistically significant difference between the two treatment arms, with HR of 0.93 (95% CI: 0.61, 1.41; p-value = 0.72).  The difference in ORR per independent central review was 18% (CI: 0.6%, 35.3%) between the two treatment arms in the few patients who had evaluable tumor at baseline and had a confirmed response prior to receiving any local therapy : 27/75 patients (36.0%, 95% CI: 25.2%, 47.9%) in the Chemo arm and 34/63 patients (54.0%, 95% CI: 40.9%, 66.6%) in the Bv + Chemo arm. The secondary endpoint of Overall Survival (OS) was not mature . Until mature OS results are available No definitive conclusion can be drawn on the benefit/risk balance.

 

Addition of Avastin to standard of care did not demonstrate clinical benefit in clinical trial BO20924, in 71 evaluable children (from age 6 months to less than 18 years old) patients with metastatic Rhabdomyosarcoma and non-Rhabdomyosarcoma Soft Tissue Sarcoma

(see section 4.2 for information on paediatric use).

 

The incidence of AEs, including Grade ³ 3 AEs and SAEs, was similar between the two treatment arms.  No AEs leading to death occurred in either treatment arm; all deaths were attributed to disease progression.  Bevacizumab addition to multimodal standard of care treatment seemed to be tolerated in this paediatric population.

 

Accordingly, at time of the primary endpoint final anaylsis, the benefit/risk balance of  the addition of Bevacizumab to standard of care in paediatric patients with metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma is not established yet.


5.2          Pharmacokinetic properties

[…]

Paediatric population

The pharmacokinetics of bevacizumab were evaluated in 152 have been studied in a limited number of paediatric patients . (7 months to 21 years, 5.9 to 125kg) across 4 clinical studies in paediatrics using a population pharmacokinetic model. The resulting pharmacokinetic results show data suggest that the clearance and volume of distribution and clearance of bevacizumab were comparable to that in adults with solid tumours between paediatric and adult patients when normalized by body weight. Age was not associated with the pharmacokinetics of bevacizumab when body weight was taken into account.

 

In Study BO20924, the pharmacokinetics of bevacizumab was well characterized by the pediatric population PK model in 70 paediatric patients (1.4 to 17.6 years; 11.6 to 77.5 kg). Based on population PK model simulations, bevacizumab exposure was generally lower in paediatric patients from Study BO20924 as compared to a typical adult patient  at the same dose, and trended lower as body weight decreased.


10.          DATE OF REVISION OF THE TEXT

 

15 September 2016

 

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:02-06-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike-through deleted:

4.1          Therapeutic indications

[…]

Bevacizumab, in combination with erlotinib, is indicated for first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations (see Section 5.1).

[…]

4.2          Posology and method of administration

[…]

Non-small cell lung cancer (NSCLC)

 

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy

 

Avastin is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by Avastin as a single agent until disease progression.

The recommended dose of Avastin is 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.

Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses (see section 5.1).

It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity.

 

First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination with erlotinib

 

EGFR mutation testing should be performed prior to initiation of treatment with the combination of Avastin and erlotinib. It is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.

The recommended dose of Avastin when used in addition to erlotinib is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.

It is recommended that the treatment with Avastin in addition to erlotinib is continued until disease progression.

 

For the posology and method of administration of erlotinib, pPlease refer to the full erlotinib prescribing information for erlotinib for patient selection and posology.

[…]

4.5          Interaction with other medicinal products and other forms of interaction

 

Effect of antineoplastic agents on bevacizumab pharmacokinetics

No clinically relevant pharmacokinetic interaction of co-administered chemotherapy on Avastin bevacizumab pharmacokinetics has been  was observed based on the results of a population PK pharmacokineticanalysis analyses. There was were neither statistically significantce nor clinically relevant differences in bevacizumab clearance of Avastin in patients receiving Avastin monotherapy compared to patients receiving Avastin in combination with interferon alfa-2a, erlotinib or other chemotherapies (IFL, 5-FU/LV, carboplatin/paclitaxel, capecitabine, doxorubicin or cisplatin/gemcitabine).

 

Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents

No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics of co-administered interferon alpha 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapies irinotecan (and its active metabolite SN38), capecitabine, oxaliplatin (as determined by measurement of free and total platinum), and cisplatin. Conclusions on the impact of bevacizumab on gemcitabine pharmacokinetics cannot be drawn.

 

Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN38.

 

Results from one trial in metastatic colorectal cancer patients demonstrated no significant effect of bevacizumab on the pharmacokinetics of capecitabine and its metabolites, and on the pharmacokinetics of oxaliplatin, as determined by measurement of free and total platinum.

 

Results from one trial in renal cancer patients demonstrated no significant effect of bevacizumab on the pharmacokinetics of interferon alfa-2a.

 

The potential effect of bevacizumab on the pharmacokinetics of cisplatin and gemcitabine was investigated in non-squamous NSCLC patients. Trial results demonstrated no significant effect of bevacizumab on the pharmacokinetics of cisplatin. Due to high inter-patient variability and limited sampling, the results from that trial do not allow firm conclusions to be drawn on the impact of bevacizumab on gemcitabine pharmacokinetics.

[…]

4.8          Undesirable effects

[…]

Some of the adverse reactions are reactions commonly seen with chemotherapy; however, Avastin may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with paclitaxel, and paronychia with erlotinib.

[…]

Hypertension (see section 4.4)

In clinical trials, with the exception of study JO25567, the overall An increased incidence of hypertension (all gGrades) ranged of up to 42.1% has been observed in Avastin-treated patients in clinical trials in the Avastin containing arms compared with up to 14% in the control arms those treated with comparator. The overall incidence of NCI-CTC Grade 3 and 4 hypertension (requiring oral anti‑hypertensive medicines) in patients receiving Avastin ranged from 0.4% to 17.9%. Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with Avastin and chemotherapy compared to up to 0.2% of patients treated with the same chemotherapy alone (NCI-CTCAE v.3).

 

In study JO25567, all grade hypertension was observed in 77.3% of the patients who received Avastin in combination with erlotinib as first-line treatment for non-squamous NSCLC with EGFR activating mutations, compared to 14.3% of patients treated with erlotinib alone. Grade 3 hypertension was 60.0% in patients treated with Avastin in combination with erlotinib compared to 11.7% in patients treated with erlotinib alone. There were no grade 4 or 5 hypertension events.

[…]

In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the Avastin containing arms compared with up to 1.7% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving Avastin compared to 0.5% in patients receiving chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) were reported in up to 2.72.3% of patients treated with Avastin in combination with chemotherapy compared to up to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was reported in up to 1.4% of patients treated with Avastin in combination with chemotherapy compared to up to 0.7% of patients treated with chemotherapy alone.

5.1          Pharmacodynamic properties

[…]

Non-small cell lung cancer (NSCLC)

 

First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy

 

[…]

First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination with erlotinib

 

JO25567

Study JO25567 was a randomized, open-label, multi-center Phase II study conducted in Japan to evaluate the efficacy and safety of Avastin used in addition to erlotinib in patients with non-squamous NSCLC with EGFR activating mutations (exon 19 deletion or exon 21 L858R mutation) who had not received prior systemic therapy for Stage IIIB/IV or recurrent disease.

The primary endpoint was progression-free survival (PFS) based on independent review assessment. Secondary endpoints included overall survival, response rate, disease control rate, duration of response, and safety and Health Related Quality of Life based on the FACT-L (Functional Assessment of Cancer Therapy for Patients with Lung Cancer) questionnaire.

EGFR mutation status was determined for each patient prior to patient screening and 154 patients were randomised to receive either erlotinib + Avastin (erlotinib 150 mg oral daily + Avastin [15 mg/kg IV every 3 weeks]) or erlotinib monotherapy (150 mg oral daily) until disease progression (PD) or unacceptable toxicity. In the absence of PD, discontinuation of one component of study treatment in the erlotinib + Avastin arm did not lead to discontinuation of the other component of study treatment as specified in the study protocol.

 

The efficacy results of the study are presented in Table 14.

Table 14                     Efficacy results for study JO25567

 

Erlotinib

N = 77#

Erlotinib + Avastin

N = 75#

PFS^ (months)

Median

 

9.7

 

16.0

HR (95% CI)

p-value

0.54 (0.36; 0.79)

0.0015

Overall Response Rate

Rate (n)

p-value

 

63.6% (49)

 

69.3% (52)

0.4951

Duration of Response (months)

Median

 

9.3

 

13.3

HR (95% CI)

p-value

0.68 (0.43; 1.10)

0.118

Disease Control Rate

Rate

p-value

 

88.3%

 

98.7%

0.0177

Overall Survival* (months)

Median

 

48.5NR

 

48.4NR

HR (95% CI)

p-value

0.91 (0.56; 1.46)1.04 (0.61- 1.77)

0.68380.8926

# A total of 154 patients ​​(ECOG Performance Status  0 or 1)  were randomized. However two of the randomized patients discontinued the study before receiving any study treatment

^ Blinded independent review (protocol-defined primary analysis)

* Exploratory analysis; OS updated analysis at clinical cut-off  on Nov 201428 October 2015, approx. 4535% patient had died and OS is therefore considered immature.

CI, confidence interval; HR, Hazard ratio from unstratified Cox regression analysis; NR, not reached.

 

In the open label study JO25567, Health Related Quality of life (HRQoL) was assessed by the FACT-L total and trial outcome index (TOI) scores and lung cancer symptoms, as assessed by the FACT-L lung cancer symptom subscale (LCS). During the progression-free time, mean baseline FACT-L scores were maintained in both treatment arms. There were no clinically meaningful differences in the FACT-L HRQoL observed between the two treatment arms. Of note, patients in the erlotinib + Avastin arm were treated for a longer duration and received intravenous administration of Avastin as opposed to oral erlotinib monotherapy in the control arm.

[…]

 

10.          DATE OF REVISION OF THE TEXT

02 June 2016

 

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:28-04-2016

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4.8       Undesirable effects

 

Summary of the safety profile

 

The overall safety profile of Avastin is based on data from over 5,4200 patients with various malignancies, predominantly treated with Avastin in combination with chemotherapy in clinical trials.

 

[ … ]

 

Description of selected serious adverse reactions

 

Gastrointestinal (GI) perforations and Fistulae (see section 4.4)

Avastin has been associated with serious cases of gastrointestinal perforation. Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% in patients with metastatic breast cancer or non-squamous non-small cell lung cancer,  up to 1.3% in patients with metastatic breast cancer,  up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer receiving front-line treatment, and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer.

 

[ … ]

 

 

Thromboembolism (see section 4.4)

 

Arterial thromboembolism: An increased incidence of arterial thromboembolic reactions was observed in patients treated with Avastin across indications, including cerebrovascular accidents, myocardial infarction, transient ischaemic attacks, and other arterial thromboembolic reactions.

 

In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the Avastin containing arms compared with up to 2.11.7% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of patients receiving Avastin compared to 0.5% in patients receiving chemotherapy alone. Cerebrovascular accidents (including transient ischaemic attacks) were reported in up to 2.3% of patients treated with Avastin in combination with chemotherapy compared to 0.5% of patients treated with chemotherapy alone. Myocardial infarction was reported in 1.4% of patients treated with Avastin in combination with chemotherapy compared to 0.7% of patients treated with chemotherapy alone.

 

[ … ]

 

10.       DATE OF REVISION OF THE TEXT

 

28 April 2016

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:22-10-2015

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4.4          Special warnings and precautions for use

[…]

Proteinuria (see section 4.8)

Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with Avastin. There is evidence suggesting that all Grade (US National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE v.3]) proteinuria may be related to the dose. Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of patients treated with Avastin. Therapy should be permanently discontinued in patients who develop Grade 4 proteinuria (nephrotic syndrome) (NCI-CTCAE v.3).

[…]

4.8          Undesirable effects

[…]

Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was reported in up to 8.1% of treated patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. The proteinuria seen in clinical trials was not associated with renal dysfunction and rarely required permanent discontinuation of therapy. Testing for proteinuria is recommended prior to start of Avastin therapy. In most clinical trials urine protein levels of ³ 2g/24 hrs led to the holding of Avastin until recovery to < 2g/24 hrs.

[…]

Clinical trials have shown that transient increases in serum creatinine (ranging between 1.5-1.9 times baseline level), both with and without proteinuria, are associated with the use of Avastin. The observed increase in serum creatinine was not associated with a higher incidence of clinical manifestations of renal impairment in patients treated with Avastin.

[…]

10.          DATE OF REVISION OF THE TEXT

22 October 2015

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:23-07-2015

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Underlined text has been added, text with strike-through deleted:

 

4.2          Posology and method of administration

[…]

Paediatric population

 

The safety and efficacy of bevacizumab in children and adolescents have not been established. Avastin is not approved for use in patients under the age of 18 years. There is no relevant use of bevacizumab in the paediatric population in the granted indications. Currently available data are described in sections 4.8, 5.1, 5.2 and 5.3 but no recommendation on a posology can be made.

Avastin should not be used in children aged 3 years to less than 18 years with recurrent or progressive high-grade glioma because of efficacy concerns (see section 5.1 for results of paediatric trials).

[…]

 

4.4          Special warnings and precautions for use

In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

[…]

 

4.8          Undesirable effects

[…]

Frequency not known:  Non-mandibular osteonecrosisa,f

f Observed in pediatric population only

[…]

Paediatric population

The safety of Avastin in children and adolescents has not been established. Avastin is not approved for use in patients under the age of 18 years. In published literature reports, cases of non-mandibular osteonecrosis have been observed in patients under the age of 18 years treated with Avastin (see section 5.3).

[…]

Musculoskeletal and connective tissue disorders

Cases of Oosteonecrosis of the Jjaw (ONJ) have been reported in patients treated with Avastin, most of which occurred in patients who had identified risk factors for ONJ, in particular exposure to intravenous bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also section 4.4)

Cases of non-mandibular osteonecrosis have been observed in Avastin treated paediatric patients (see section 4.8, Paediatric population).

 

[…]

10.          DATE OF REVISION OF THE TEXT

 

23 July 2015

 

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:30-03-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike through deleted:

4.1          Therapeutic indications

[…]

Bevacizumab, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix (see Section 5.1).

 

4.2          Posology and method of administration

[…]

Cervical Cancer

Avastin is administered in combination with one of the following chemotherapy regimens: paclitaxel and cisplatin or paclitaxel and topotecan.

The recommended dose of Avastin is 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion.

It is recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity (see section 5.1).

[…]

4.4          Special warnings and precautions for use

In order to improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient file.

Gastrointestinal (GI) perforations and Fistulae (see section 4.8)

Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation when treated with Avastin. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when treating these patients. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or metastatic cervical cancer with Avastin and all patients with GI perforation had a history of prior radiation. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation.

 

GI-vaginal Fistulae in study GOG-0240

Patients treated for persistent, recurrent, or metastatic cervical cancer with Avastin are at increased risk of fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal fistulae). Prior radiation is a major risk factor for the development of GI-vaginal fistulae and all patients with GI-vaginal fistulae had a history of prior radiation. Recurrence of cancer within the field of prior radiation is an additional important risk factor for the development of GI-vaginal fistulae.

 

Non-GI Fistulae (see section 4.8)

Patients may be at increased risk for the development of fistulae when treated with Avastin.

Permanently discontinue Avastin in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula [US National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v.3)]. Limited information is available on the continued use of Avastin in patients with other fistulae.
In cases of internal fistula not arising in the gastrointestinal (GI) tract, discontinuation of Avastin should be considered.

[…]

 

Venous thromboembolism (see section 4.8)

Patients may be at risk of developing venous thromboembolic reactions, including pulmonary embolism under Avastin treatment.

Patients treated for  persistent, recurrent, or metastatic cervical cancer with Avastin in combination with paclitaxel and cisplatin may be at increased risk of venous thromboembolic events.

Avastin should be discontinued in patients with life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism (NCI-CTCAE v.3). Patients with thromboembolic reactions ≤ Grade 3 need to be closely monitored (NCI-CTCAE v.3).

[…]

Neutropenia and infections (see section 4.8)

Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus Avastin in comparison to chemotherapy alone. This has mainly been seen in combination with platinum- or taxane-based therapies in the treatment of NSCLC, and mBC, and in combination with paclitaxel and topotecan in persistent, recurrent, or metastatic cervical cancer.

[…]

4.8          Undesirable effects

[…]

Table 1: Adverse Reactions by Frequency

 

System organ class

Very Common

Common

Uncommon

Rare

Very Rare

Frequency Not Known

Infections and infestations

 

Sepsis,

Abscessb,d,

Cellulitis, Infection,

Urinary tract infection

 

Necrotising

fasciitis a

 

 

Blood and lymphatic system disorders

Febrile

neutropenia,

Leucopenia,

Neutropeniab,

Thrombo-cytopenia

Anaemia, Lymphopenia

 

 

 

 

Immune system disorders

 

Hypersensitivity, infusion reactionsa,b,d

 

 

 

 

Metabolism and nutrition disorders

Anorexia

Dehydration

 

 

 

 

Nervous system disorders

Peripheral sensory

neuropathyb,

Dysarthria,

Headache,

Dysguesia

Cerebrovascular

accident,

Syncope,

Somnolence

 

 

Posterior

reversible

encephalo-

pathy

syndrome a,b,d

Hypertensive

encephalo-

pathya

 

Eye disorders

 

 

Eye disorder,

Lacrimation increased

 

 

 

 

 

Cardiac disorders

 

Congestive heart

failureb,d,

Supraventricular

 tachycardia

 

 

 

 

Vascular disorders

Hypertensionb,d,

Thrombo-embolism

(venous)b,d

Thrombo-embolism

(arterial)b,d,

Haemorrhageb,d,

Deep vein

thrombosis

 

 

 

Renal

thrombotic

microangiopathya,b

Respiratory, thoracic and mediastinal disorders

Dyspnoea,

Rhinitis

Pulmonary

haemorrhage/

Haemoptysisb,d,

Pulmonary

embolism,

Epistaxis,

Hypoxia,

Dysphoniaa

 

 

 

Pulmonary

hypertensiona,

Nasal septum

perforationa

Gastrointestinal disorders

Rectal

haemorrhage,

Stomatitis,

Constipation,

Diarrhoea,

Nausea,

Vomiting, Abdominal pain

Gastrointestinal  perforationb,d,

Intestinal

perforation,

Ileus,

Intestinal

obstruction,

Abdominal pain,Recto-vaginal fistulaed,e,

Gastrointestinal

Disorder,

Proctalgia

 

 

 

Gastrointestinal

ulcera

Hepatobiliary disorders

 

 

 

 

 

Gallbladder perforationa,b

Skin and subcutaneous tissue disorders

Wound healing

complicationsb,d,

Exfoliative

dermatitis,

Dry skin,

Skin discoloration

Palmar-plantar

erythro-dysaesthesia

syndrome

 

 

 

 

 

Musculoskeletal  and connective tissue disorders

Arthralgia

Fistulab,d,

Myalgia,

Muscular weakness,

Back pain

 

 

 

Osteonecrosis of the jawa,b

Renal and urinary disorders

Proteinuriab,d

 

 

 

 

 

Reproductive system and breast disorders

Ovarian

failureb,c,d 

 

Pelvic Pain

 

 

 

 

Congenital, familial, and genetic disorder

 

 

 

 

 

Foetal abnormalitiesa,b

General disorders and administration site conditions

Asthenia,

Fatigue,

Pyrexia,

Pain,

Mucosal inflammation

Lethargy

 

 

 

 

 

Investigations

Weight decreased

 

 

 

 

 

 

 When events were noted as both all grade and grade 3-5 adverse drug reactions in clinical trials, the highest frequency observed in patients has been reported. Data are unadjusted for the differential time on treatment. 

 

a For further information please refer to Table 3 'Adverse reactions reported in post-marketing setting.'

 

b Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary for Regulatory Activities) preferred term.  This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).

 

 

c Based on a substudy from NSABP C-08 with 295 patients

 

 

 

d For additional information refer below within section "Further information on selected serious adverse reactions."

e Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.

 

 

Table 2: Severe Adverse Reactions by Frequency

 

System organ class

Very Common

Common

Uncommon

Rare

Very Rare

Frequency Not Known

Infections and infestations

 

Sepsis,

Cellulitis,

Abscessa,b,

Infection,

Urinary tract infection

 

 

 

Necrotising

fasciitisc

Blood and lymphatic system disorders

Febrile

neutropenia,

Leucopenia,

Neutropeniaa,

Thrombo-cytopenia

Anaemia, Lymphopenia

 

 

 

 

Immune system disorders

 

 

 

 

 

Hypersensitivity, infusion reactions a,b,c

Metabolism and nutrition disorders

 

Dehydration

 

 

 

 

Nervous system disorders

 

Peripheral sensory

neuropathya

Cerebrovascular

accident,

Syncope,

Somnolence,

Headache

 

 

 

Posterior

reversible

encephalo-

pathy

syndrome a,b,c,

Hypertensive

encephalo-

pathyc 

Cardiac disorders

 

Congestive heart

failurea,b,

Supraventricular

tachycardia

 

 

 

 

Vascular disorders

Hypertensiona,b

Thromboembolism arteriala,b,

Haemorrhagea,b,

Thromboembolism

(venous)a,b

Deep vein

thrombosis

 

 

 

Renal

thrombotic

microangiopathyb,c

Respiratory, thoracic and mediastinal disorders

 

Pulmonary

haemorrhage/

Haemoptysisa,b,

Pulmonary

embolism,

Epistaxis,

Dyspnoea,

Hypoxia

 

 

 

Pulmonary

hypertensionc,

Nasal septum

perforationc

Gastrointestinal disorders

Diarrhoea,

Nausea,

Vomiting,

Abdominal pain

Intestinal

perforation,

Ileus,

Intestinal

obstruction,

Recto-vaginal fistulaec,d

Abdominal pain,,

Gastrointestinal

disorder,

Stomatitis,

Proctalgia

 

 

 

 

Gastrointestinal

perforationa,b,

Gastrointestinal

ulcerc,

Rectal haemorrhage

 

Hepatobiliary disorders

 

 

 

 

 

Gallbladder perforation b,c

Skin and subcutaneous tissue disorders

 

Wound healing

complicationsa,b,

Palmar-plantar

erythrodysaesthesia

syndrome

 

 

 

 

Musculoskeletal and connective tissue disorders

 

Fistulaa,b,

Myalgia,

Arthralgia,

Muscular weakness,

Back Pain

 

 

 

Fistulaa,b,

Osteonecrosis of the jawb,c

Renal and urinary disorders

 

Proteinuriaa,b

 

 

 

 

 

Reproductive system and breast disorders

 

Pelvic pain

 

 

 

Ovarian failurea,b

Congenital, familial, and genetic disorder

 

 

 

 

 

Foetal abnormalitiesa,c

General disorders and administration site conditions

Asthenia,

Fatigue,

Pain,

Lethargy,

Mucosal

Inflammation

 

 

 

 

 

Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 reactions. Table 2 also includes adverse reactions which are considered by the MAH to be clinically significant or severe.  These clinically significant adverse reactions were reported in clinical trials but the grade 3-5 reactions did not meet the threshold of at least a 2% difference compared to the control arm. Table 2 also includes clinically significant adverse reactions that were observed only in the postmarketing setting, therefore, the frequency and NCI-CTCAE grade  is not known.These clinically significant reactions have therefore been included in Table 2 within the column entitled “Frequency Not Known.”

a Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial infarction, transient ischaemic attack and other arterial thromboembolic reactions).

b For additional information refer below within section "Further information on selected serious adverse reactions"

c For further information please refer to Table 3 'Adverse reactions reported in post-marketing setting.'

d Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category.

 

Description of selected serious adverse reactions

 

Gastrointestinal (GI) perforations and Fistulae (see section 4.4)

Avastin has been associated with serious cases of gastrointestinal perforation.

 

Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% in patients with metastatic breast cancer or non-squamous non-small cell lung cancer, up to 2.0% in patients with metastatic renal cell cancer or in patients with ovarian cancer receiving front-line treatment, and up to 2.7% (including gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which represents between 0.2%-1% of all Avastin treated patients. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), GI perforations (all grade) were reported in 3.2% of patients, all of whom had a history of prior pelvic radiation.

 

The occurrence of those eventspresentation of these reactions varied in type and severity, ranging from free air seen on the plain abdominal X‑ray, which resolved without treatment, to intestinal perforation with abdominal abscess and fatal outcome. In some cases underlying intra‑abdominal inflammation was present, either from gastric ulcer disease, tumour necrosis, diverticulitis, or chemotherapy-associated colitis.

 

Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which represents between 0.2%-1% of all Avastin treated patients.

 

In Avastin clinical trials, gastrointestinal fistulae (all grade) have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported less commonly in patients with other types of cancer.

 

GI-vaginal Fistulae in study GOG-0240

In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal fistulae was 8.3% in Avastin‑treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. The frequency of GI-vaginal fistulae in the group treated with Avastin + chemotherapy was higher in patients with recurrence within the field of prior radiation (16.7%) compared with patients with recurrence outside the field of prior radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 1.1% vs. 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical intervention as well as diverting ostomies.

 

Non-GI Fistulae (see section 4.4)

Avastin use has been associated with serious cases of fistulae including reactions resulting in death.

 

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-240), 1.8% of Avastin‑treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, vesical, or female genital tract fistulae.

 

In clinical trials, gastrointestinal fistulae have been reported with an incidence of up to 2% in patients with metastatic colorectal cancer and ovarian cancer, but were also reported less commonly in patients with other types of cancers. In a study of platinum resistant ovarian cancer (study MO22224), an incidence of up to 2.2% of fistulae involving the urinary bladder and female genital tract (including rectovaginal fistulae) was observed. Uncommon (³ 0.1% to < 1%) reports of other types of fistulae that involve areas of the body other than the gastrointestinal tract (e.g. bronchopleural and biliary fistulae) were observed across various indications. Fistulae have also been reported in post-marketing experience.

[…]

Haemorrhage (see section 4.4)

In clinical trials across all indications the overall incidence of NCI-CTCAE v.3 Grade 3-5 bleeding reactions ranged from 0.4% to 6.9%6.5% in Avastin treated patients, compared with up to 4.5%2.9% of patients in the chemotherapy control group.

 

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 bleeding reactions have been reported in up to 8.3% of patients treated with Avastin in combination with paclitaxel and topotecan compared with up to 4.6% of patients treated with paclitaxel and topotecan.

[…]

Grade 3-5 (NCI-CTCAE v.3) venous thromboembolic reactions have been reported in up to 7.8% of patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treated with chemotherapy alone (across indications, excluding persistent, recurrent, or metastatic cervical cancer).

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 venous thromboembolic events have been reported in up to 15.6% of patients treated with Avastin in combination with paclitaxel and cisplatin compared with up to 7.0% of patients treated with paclitaxel and cisplatin.

[…]

Infections

From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 infections have been reported in up to 24% of patients treated with Avastin in combination with paclitaxel and topotecan compared with up to 13% of patients treated with paclitaxel and topotecan.

[…]

5.1          Pharmacodynamic properties

[…]

Cervical Cancer

 

GOG-0240

The efficacy and safety of Avastin in combination with chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) in the treatment for patients with persistent, recurrent or metastatic carcinoma of the cervix was evaluated in study GOG-0240, a randomised, four-arm, open label, multi-centre phase III trial.

 

A total of 452 patients were randomised to receive either:

 

·      Paclitaxel 135 mg/m2 IV over 24 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2, every 3 weeks (q3w); or

Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2 (q3w); or

Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 1 (q3w)

 

·      Paclitaxel 135 mg/m2 IV over 24 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2 plus bevacizumab 15 mg/kg IV on Day 2 (q3w); or

Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2 plus bevacizumab 15 mg/kg IV on Day 2 (q3w); or

Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 1 plus bevacizumab 15 mg/kg IV on Day 1 (q3w)

 

·      Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1-3 (q3w)

 

·      Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on Days 1-3 plus bevacizumab 15 mg/kg IV on Day 1 (q3w)

 

Eligible patients had persistent, recurrent or metastatic squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix which was not amenable to curative treatment with surgery and/or radiation therapy and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents.

The median age was 46.0 years (range: 20-83) in the Chemo alone group and 48.0 years (range: 22-85) in the Chemo+Avastin group; with 9.3% of patients in the Chemo alone group and 7.5% of patients in the Chemo+Avastin group over the age of 65 years.

Of the 452 patients randomized at baseline, the majority of patients were white (80.0% in the Chemo alone group and 75.3% in the Chemo+Avastin group), had squamous cell carcinoma (67.1% in the Chemo alone group and 69.6% in the  Chemo+Avastin group), had persistent/recurrent disease (83.6% in the Chemo alone group and 82.8% in the  Chemo+Avastin group), had 1-2 metastatic sites (72.0% in the Chemo alone group and 76.2% in the  Chemo+Avastin group), had lymph node involvement (50.2% in the Chemo alone group and 56.4% in the  Chemo+Avastin group), and had a platinum free interval  ³  6 months (72.5% in the Chemo alone group and 64.4% in the  Chemo+Avastin group).

 

The primary efficacy endpoint was overall survival. Secondary efficacy endpoints included progression-free survival and objective response rate. Results from the primary analysis and the follow-up analysis are presented by Avastin Treatment and by Trial Treatment in Table 23 and Table 24, respectively.

 

Table 23               Efficacy results from study GOG-0240 by Avastin Treatment

 

 

Chemotherapy

(n=225)

Chemotherapy + Avastin

(n=227)

Primary Endpoint

Overall Survival – Primary analysis6

Median (months)1

12.9                           

16.8

Hazard ratio [95% CI]

0.74 [0.58, 0.94]

(p-value5 = 0.0132)

Overall Survival – Follow-up analysis7

Median (months)1

13.3                        

16.8

Hazard ratio [95% CI]

0.76 [0.62, 0.94]

(p-value5,8 = 0.0126)

Secondary Endpoints

Progression-free survival – Primary analysis6

Median PFS (months)1

6.0

8.3

Hazard ratio [95% CI]

0.66 [0.54, 0.81]

(p-value5 <0.0001)

Best Overall Response – Primary analysis6

Responders (Response rate2)

76 (33.8 %)                  

103 (45.4 %)

95% CI for Response Rates3               

[27.6%, 40.4%]                  

[38.8%, 52.1%]

Difference in Response Rates                                 

11.60%

95% CI for Difference in Response Rates4

[2.4%, 20.8%]

p-value (Chi-squared Test)

0.0117

1 Kaplan-Meier estimates

2 Patients and percentage of patients with best overall response of confirmed CR or PR; percentage calculated on patients with measurable disease at baseline  

3 95% CI for one sample binomial using Pearson-Clopper method

4 Approximate 95% CI for difference of two rates using Hauck-Anderson method

5 log-rank test (stratified)

6 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final analysis

7 Follow-up analysis was performed with a data cut-off date of 07 March 2014

8 p-value displayed for descriptive purpose only

 

 

Table 24               Overall survival results from study GOG-0240 by Trial Treatment

 

Treatment Comparison

Other Factor

Overall survival – Primary analysis1

Hazard Ratio (95% CI)

Overall survival - Follow-up analysis2

Hazard Ratio (95% CI)

Avastin vs. No Avastin

Cisplatin+ Paclitaxel

0.72 (0.51, 1.02)

(17.5 vs.14.3 months; p = 0.0609)

0.75 (0.55, 1.01)

(17.5 vs.15.0 months; p = 0.0584)

Topotecan+ Paclitaxel

0.76 (0.55, 1.06)

(14.9 vs. 11.9 months; p = 0.1061)

0.79 (0.59, 1.07)

(16.2 vs. 12.0 months; p = 0.1342)

 

 

 

 

Topotecan+ Paclitaxel vs. Cisplatin+ Paclitaxel

Avastin

1.15 (0.82, 1.61)

(14.9 vs. 17.5 months; p = 0.4146)

1.15 (0.85, 1.56)

(16.2 vs 17.5 months; p = 0.3769)

No Avastin

1.13 (0.81, 1.57)

(11.9 vs.14.3 months; p = 0.4825)

1.08 (0.80, 1.45)

(12.0 vs 15.0 months; p = 0.6267)

1 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final analysis

2 Follow-up analysis was performed with a data cut-off date of 07 March 2014; all p-values are displayed for descriptive purpose only

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies, in all subsets of the paediatric population, in breast carcinoma, adenocarcinoma of the colon and rectum, lung carcinoma (small cell and non-small cell carcinoma), kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney), ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumours), fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumours), and peritoneal carcinoma (excluding blastomas and sarcomas) and cervix and corpus uteri carcinoma.

[…]

5.3          Preclinical safety data

[…]

Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits. Observed effects included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an increased incidence of specific gross and skeletal foetal malformations. Adverse foetal outcomes were observed at all tested doses, of which the lowest dose resulted in average serum concentrations approximately 3 times larger than in humans receiving 5 mg/kg every 2 weeks. Information on foetal malformations observed in the post marketing setting are provided in section 4.6 Fertility, Pregnancy and Lactation and 4.8 Undesirable Effects.

 

9.            DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 12 January 2005

Date of latest renewal: 14 January 20150

 

10.          DATE OF REVISION OF THE TEXT

30 March 2015

 

 

 

Reasons for adding or updating:

  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.3 - Preclinical safety data
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:26-02-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike-through deleted:

4.6          Fertility, pregnancy and lactation

 

Women of childbearing potential

Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment.

Pregnancy

There are no clinical trial data on the use of Avastin in pregnant women. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). IgGs are known to cross the placenta, and Avastin is anticipated to inhibit angiogenesis in the foetus, and thus is suspected to cause serious birth defects when administered during pregnancy. In the post-marketing setting, cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see section 4.8). Avastin is contraindicated in pregnancy (see section 4.3).

[…]

4.8          Undesirable effects

[…]

Table 1: Adverse Reactions by Frequency

System organ class

Very Common

Common

Uncommon

Rare

Very Rare

Frequency Not Known

Infections and infestations

 

Sepsis,

Abscessb,d,

Infection,

Urinary tract infection

 

Necrotising

fasciitis a

 

 

Blood and lymphatic system disorders

Febrile

neutropenia,

Leucopenia,

Neutropeniab,

Thrombo-cytopenia

Anaemia

 

 

 

 

Immune system disorders

 

Hypersensitivity, infusion reactionsa,b,d

 

 

 

 

Metabolism and nutrition disorders

Anorexia

Dehydration

 

 

 

 

Nervous system disorders

Peripheral sensory

neuropathyb,

Dysarthria,

Headache,

Dysguesia

Cerebrovascular

accident,

Syncope,

Somnolence

 

 

Posterior

reversible

encephalo-

pathy

syndrome a,b,d

Hypertensive

encephalo-

pathya

 

Eye disorders

 

 

Eye disorder,

Lacrimation increased

 

 

 

 

 

Cardiac disorders

 

Congestive heart

failureb,d,

Supraventricular

 tachycardia

 

 

 

 

Vascular disorders

Hypertensionb,d,

Thrombo-embolism

(venous)b,d

Thrombo-embolism

(arterial)b,d,

Haemorrhageb,d,

Deep vein

thrombosis

 

 

 

Renal

thrombotic

microangiopathya,b

Respiratory, thoracic and mediastinal disorders

Dyspnoea,

Rhinitis

Pulmonary

haemorrhage/

Haemoptysisb,d,

Pulmonary

embolism,

Epistaxis,

Hypoxia,

Dysphoniaa

 

 

 

Pulmonary

hypertensiona,

Nasal septum

perforationa

Gastrointestinal disorders

Rectal

haemorrhage,

Stomatitis,

Constipation,

Diarrhoea,

Nausea,

Vomiting

Gastrointestinal  perforationb,d,

Intestinal

perforation,

Ileus,

Intestinal

obstruction,

Abdominal pain,

Gastrointestinal

disorder

 

 

 

Gastrointestinal

ulcera

Hepatobiliary disorders

 

 

 

 

 

Gallbladder perforationa,b

Skin and subcutaneous tissue disorders

Wound healing

complicationsb,d,

Exfoliative

dermatitis,

Dry skin,

Skin discoloration

Palmar-plantar

erythro-dysaesthesia

syndrome

 

 

 

 

 

Musculoskeletal  and connective tissue disorders

Arthralgia

Fistulab,d,

Myalgia,

Muscular weakness

 

 

 

Osteonecrosis of the jawa,b

Renal and urinary disorders

Proteinuriab,d

 

 

 

 

 

Reproductive system and breast disorders

Ovarian

failureb,c,d 

 

 

 

 

 

 

Congenital, familial, and genetic disorder

 

 

 

 

 

Foetal abnormalitiesa,b

[…]

Table 2: Severe Adverse Reactions by Frequency

System organ class

Very Common

Common

Uncommon

Rare

Very Rare

Frequency Not Known

Infections and infestations

 

Sepsis,

Abscessa,b,

Infection,

Urinary tract infection

 

 

 

Necrotising

fasciitisc

Blood and lymphatic system disorders

Febrile

neutropenia,

Leucopenia,

Neutropeniaa,

Thrombo-cytopenia

Anaemia

 

 

 

 

Immune system disorders

 

 

 

 

 

Hypersensitivity, infusion reactions a,b,c

Metabolism and nutrition disorders

 

Dehydration

 

 

 

 

Nervous system disorders

 

Peripheral sensory

neuropathya

Cerebrovascular

accident,

Syncope,

Somnolence,

Headache

 

 

 

Posterior

reversible

encephalo-

pathy

syndrome a,b,c,

Hypertensive

encephalo-

pathyc 

Cardiac disorders

 

Congestive heart

failurea,b,

Supraventricular

tachycardia

 

 

 

 

Vascular disorders

Hypertensiona,b

Thromboembolism arteriala,b,

Haemorrhagea,b,

Thromboembolism

(venous)a,b

Deep vein

thrombosis

 

 

 

Renal

thrombotic

microangiopathyb,c

Respiratory, thoracic and mediastinal disorders

 

Pulmonary

haemorrhage/

Haemoptysisa,b,

Pulmonary

embolism,

Epistaxis,

Dyspnoea,

Hypoxia

 

 

 

Pulmonary

hypertensionc,

Nasal septum

perforationc

Gastrointestinal disorders

Diarrhoea,

Nausea,

Vomiting

Intestinal

perforation,

Ileus,

Intestinal

obstruction,

Abdominal pain,

Gastrointestinal

disorder,

Stomatitis

 

 

 

Gastrointestinal

perforationa,b,

Gastrointestinal

ulcerc,

Rectal haemorrhage

 

Hepatobiliary disorders

 

 

 

 

 

Gallbladder perforation b,c

Skin and subcutaneous tissue disorders

 

Wound healing

complicationsa,b,

Palmar-plantar

erythrodysaesthesia

syndrome

 

 

 

 

Musculoskeletal and connective tissue disorders

 

Myalgia,

Arthralgia,

Muscular weakness

 

 

 

Fistulaa,b,

Osteonecrosis of the jawb,c

Renal and urinary disorders

 

Proteinuriaa,b

 

 

 

 

 

Reproductive system and breast disorders

 

 

 

 

 

Ovarian failurea,b

Congenital, familial, and genetic disorder

 

 

 

 

 

Foetal abnormalitiesa,c

 

System organ class

Very Common

Common

Uncommon

Rare

Very Rare

Frequency Not Known

General disorders and administration site conditions

Asthenia,

Fatigue,

Pain,

Lethargy,

Mucosal

Inflammation

 

 

 

 

 

[…]

Table 3           Adverse reactions reported in post-marketing setting

System organ class (SOC)

Reactions (frequency*)

Infections and Infestations

Necrotising fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation (rare) (see also section 4.4)

Immune system disorders

Hypersensitivity reactions and infusion reactions (not known); with the following possible co-manifestations: dyspnoea/difficulty breathing, flushing/redness/rash, hypotension or hypertension, oxygen desaturation, chest pain, rigors and nausea/vomiting (see also section 4.4 and Hypersensitivity reactions/infusion reactions above)

Nervous system disorders

Hypertensive encephalopathy (very rare) (see also section 4.4 and Hypertension in section 4.8)

Posterior Reversible Encephalopathy Syndrome (rare) (see also section 4.4)

Vascular disorders

Renal thrombotic microangiopathy, which may be clinically manifested as proteinuria (not known) with or without concomitant sunitinib use. For further information on proteinuria see section 4.4 and Proteinuria in section 4.8.

Respiratory, thoracic and mediastinal disorders

Nasal septum perforation (not known)

Pulmonary hypertension (not known)

Dysphonia (common)

Gastrointestinal disorders

Gastrointestinal ulcer (not known)

Hepatobiliary disorders

Gall bladder perforation (not known)

Immune system disorders

Hypersensitivity reactions and infusion reactions (not known); with the following possible co-manifestations: dyspnoea/difficulty breathing, flushing/redness/rash, hypotension or hypertension, oxygen desaturation, chest pain, rigors and nausea/vomiting (see also section 4.4 and Hypersensitivity reactions/infusion reactions above)

Musculoskeletal and connective tissue disorders

Cases of osteonecrosis of the jaw (ONJ) have been reported in patients treated with Avastin, most of which occurred in patients who had identified risk factors for ONJ, in particular exposure to intravenous bisphosphonates and/or a history of dental disease requiring invasive dental procedures (see also section 4.4)

Infections and Infestations

Necrotising fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation (rare) (see also section 4.4)

Congenital, familial, and genetic disorder

Cases of foetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed (see section 4.6 )

 

[…]

5.3          Preclinical safety data

 

In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed in young animals with open growth plates, at bevacizumab average serum concentrations below the expected human therapeutic average serum concentrations. In rabbits, bevacizumab was shown to inhibit wound healing at doses below the proposed clinical dose. Effects on wound healing were shown to be fully reversible.

 

Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not been performed.

 

No specific studies in animals have been conducted to evaluate the effect on fertility. An adverse effect on female fertility can however be expected as repeat dose toxicity studies in animals have shown inhibition of the maturation of ovarian follicles and a decrease/absence of corpora lutea and associated decrease in ovarian and uterus weight as well as a decrease in the number of menstrual cycles.

 

Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits. Observed effects included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an increased incidence of specific gross and skeletal foetal malformations. Adverse foetal outcomes were observed at all tested doses, of which the lowest dose resulted in average serum concentrations approximately 3 times larger than in humans receiving 5 mg/kg every 2 weeks. Information on foetal malformations observed in the post marketing setting are provided in section 4.6 Fertility, Pregnancy and Lactation and 4.8 Undesirable Effects.

 

9.            DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 12 January 2005

Date of latest renewal: 14 January 2015

 

 

10.          DATE OF REVISION OF THE TEXT

 

26 February 2015

 

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:17-11-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underlined Text = new text
Struck Through Text = deleted text

[ … ]

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each ml of concentrate contains 25 mg of bevacizumab*.

Each 4 ml vial contains 100 mg of bevacizumab, corresponding to 1.4 mg/ml when diluted as recommended.

Each 16 ml vial contains 400 mg of bevacizumab, corresponding to 16.5 mg/ml when diluted as recommended.

For dilution and other handling recommendations, see section 6.6.

 

*Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in Chinese Hamster Ovary cells.

 

For the full list of excipients, see section 6.1.

 

[ … ]

 

4.7       Effects on ability to drive and use machines

 

No studies on the effects on the ability to drive and use machines have been performed. However, there is no evidence that Avastin treatment results in an increase in adverse reactions that might lead to impairment of the ability to drive or operate machinery or impairment of mental ability. Avastin has no or negligible influence on the ability to drive and use machines. However, somnolence and syncope have been reported with Avastin use (see table 1 in section 4.8). If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate.

 

 

4.8       Undesirable effects

 

Summary of the safety profile

 

[ … ]

 

Tabulated list of adverse reactions

 

[ … ]

 

Description of Further information on selected serious adverse reactions

 

[ … ]

 

Ovarian failure/fertility (see sections 4.4 and 4.6)

In NSABP C-08, a phase III trial of Avastin in adjuvant treatment of patients with colon cancer, the incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test, has been evaluated in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% patients in the mFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluable women. Long term effects of the treatment with bevacizumab on fertility are unknown.

 

Laboratory abnormalities

Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be associated with Avastin treatment.

 

Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities occurred in patients treated with Avastin with at least a 2% difference compared to the corresponding control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, increased international normalised ratio (INR).

 

 

Other special populations

 

[ … ]

 

Ovarian failure/fertility (see sections 4.4 and 4.6)

In NSABP C-08, a phase III trial of Avastin in adjuvant treatment of patients with colon cancer, the incidence of new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test, has been evaluated in 295 premenopausal women. New cases of ovarian failure were reported in 2.6% patients in the mFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. After discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluable women. Long term effects of the treatment with bevacizumab on fertility are unknown.

 

Laboratory abnormalities

Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be associated with Avastin treatment.

 

Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities occurred in patients treated with Avastin with at least a 2% difference compared to the corresponding control groups: hyperglycaemia, decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, increased international normalised ratio (INR).

 

[ … ]

 

5.1       Pharmacodynamic properties

 

[ … ]

 

Advanced and/or metastatic renal cell cancer (mRCC)

 

Avastin in Combination combination with Interferon interferon alfa-2a for the Firstfirst-Line line Treatment treatment of Advanced advanced and/ or Metastatic metastatic Renal renal Cell cell cCancer (BO17705)

 

[ … ]

 

5.2       Pharmacokinetic properties

 

[ … ]

 

Biotransformation

Metabolism

 

[ … ]

 

6.6       Special precautions for disposal and other handling

 

Avastin should be prepared by a healthcare professional using aseptic technique to ensure the sterility of the prepared solution.

 

The necessary amount of bevacizumab should be withdrawn and diluted to the required administration volume with sodium chloride 9 mg/ml (0.9%) solution for injection. The concentration of the final bevacizumab solution should be kept within the range of 1.4 mg/ml to 16.5 mg/ml. In the majority of the occasions the necessary amount of Avastin can be diluted with 0.9 % sodium chloride solution for injection to a total volume of 100 mL.

 

[ … ]

 

10.       DATE OF REVISION OF THE TEXT

 

17 November 2014

 

[ … ]

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:25-09-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underlined text has been added: