EPVC Newsletter

Part I of II
EPVC Newsletter
March 2016
Egyptian
Pharmaceutical
Vigilance Center
(EPVC)
Pharmacovigilance
Department
Inside this issue:
13 Case Reports 1
from Tanta suffered
from loss of vision
along
with
eye
bleeding associated
with off label use of
Avastin®.
Case Report from 3
AlexandriaInflammatory hepatitis and raised liver
enzymes with DepoProvera
13 Case Reports from Tanta suffered from loss of
vision along with eye bleeding associated with off label
use of Avastin®.
The regional center in Cairo has
received a complaint concerning 13
patients who were administered
Avastin ® as treatment of Eye
Disorders such as: Macular
degeneration, diabetic retinopathy
and retinal vein occlusion which is
considered as off-label use. This led
to very serious Eye Problems.
Avastin ® (bevacizumab) is a
vascular endothelial growth factorspecific angiogenesis inhibitor
indicated for the treatment of:

Metastatic Colorectal Cancer
(mCRC).

Locally Advanced, Metastatic
or Recurrent Non-Small Cell
Lung Cancer (NSCLC)

Platinum-Sensitive Recurrent
Epithelial Ovarian, Fallopian
Tube and Primary Peritoneal
Cancer.

Platinum-Resistant Recurrent
Epithelial Ovarian, Fallopian
Tube and Primary Peritoneal
Cancer.

Malignant Glioma (WHO
Grade IV) - Glioblastoma
Case Reports from 5
Sohag
associated
with RIVO
Recall from the 5
Egyptian
market
due to counterfeit
“Batches” Recall of 7
some pharmaceutical products from
the Egyptian market
Volume 7, Issue 03
Labeled information:
According
to
Avastin
(bevacizumab) Summary of
product Characteristics (SmPC) in
EMA, it was stated under section
(4.1 Therapeutic indications) that:

Bevacizumab in combination with
fluoropyrimidine-based
chemotherapy is indicated for
treatment of adult patients with
metastatic carcinoma of the colon or
rectum.

Bevacizumab in combination with
paclitaxel is indicated for first-line
treatment of adult patients with
metastatic breast cancer.

Bevacizumab in combination with
capecitabine is indicated for firstline treatment of adult patients
with metastatic breast cancer in
whom treatment with other
chemotherapy options including
taxanes or anthracyclines is not
considered appropriate. Patients
who have received taxane and
Page 2
anthracyclinecontaining regimens in the adjuvant
setting within the last 12 months should be
excluded from treatment with Avastin in
combination with capecitabine.
 Bevacizumab, in addition to platinum-based
chemotherapy, is indicated for first-line treatment
of adult patients with unresectable advanced,
metastatic or recurrent non-small cell lung cancer
other than predominantly squamous cell histology.

Bevacizumab in combination with interferon alfa2a is indicated for first line treatment of adult
patients with advanced and/or metastatic renal
cell cancer.
 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.
 Bevacizumab, in combination with carboplatin
and gemcitabine, is indicated for treatment of
adult patients with first recurrence of platinumsensitive epithelial ovarian, fallopian tube or
primary 3 peritoneal cancer who have not received
prior therapy with bevacizumab or other VEGF
inhibitors or VEGF receptor–targeted agents.

Bevacizumab in combination with paclitaxel,
topotecan, or pegylated liposomal doxorubicin is
indicated for the treatment of adult patients with
platinum-resistant recurrent epithelial ovarian,
fallopian tube, or primary peritoneal cancer who
received no more than two prior chemotherapy
regimens and who have not received prior therapy
with bevacizumab or other VEGF inhibitors or
VEGF receptor–targeted agents.
 Bevacizumab, in combination with paclitaxel and
cisplatin or, alternatively, paclitaxel and topotecan
in patients who cannot receive platinum therapy,
Part I EPVC
Volume 7, Issue 03
is indicated for the treatment of adult patients with
persistent, recurrent, or metastatic carcinoma of the
cervix".
It was stated under section (4.4 Special
warnings and precautions for use) that :
“Individual cases and clusters of serious ocular adverse
reactions have been reported following unapproved
intravitreal use of Avastin compounded from vials
approved for intravenous administration in cancer
patients. These reactions included infectious
endophthalmitis, intraocular inflammation such as
sterile endophthalmitis, uveitis and vitritis, retinal
detachment, retinal pigment epithelial tear, intraocular
pressure increased, intraocular haemorrhage such as
vitreous haemorrhage or retinal haemorrhage and
conjunctival haemorrhage. Some of these reactions have
resulted in various degrees of visual loss, including
permanent blindness.
It was stated under section (4.8 Undesirable
effects) that:
Avastin has been developed and made to treat cancer
by injecting it into the bloodstream. It has not been
developed or made for injection into the eye. It is
therefore not authorised to be used in this way. When
Avastin is injected directly into the eye (unapproved use),
the following side effects may occur:

Infection or inflammation of the eye globe,

Redness of the eye, small particles or spots in
your vision (floaters), eye pain,

Seeing flashes of light with floaters, progressing
to a loss of some of your vision,

Increased eye pressure,

Bleeding in the eye.
According to Avastin® (Bevacizumab) Product
Information (PI) in FDA:
It was stated under section (Post marketing
Experience):
Page 3
Part I EPVC
Volume 7, Issue 03
“Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision;
Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular
pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular
hyperemia; Ocular pain or discomfort”
Regulatory Actions taken :
1. EPVC (The Egyptian Pharmaceutical Vigilance Center) requested from Roche Scientific Office in
Egypt to distribute a DHPC (Dear Healthcare Professional Communication) among the
ophthalmologists to highlight that “Avastin is not suitable for intravitreal use” and the risks of this off
label use.
Moreover Roche mentioned in the DHPC that the company didn’t perform any ocular efficacy or
safety testing with Avastin, consequently its use intravitrealy is not approved in any country in the
world.
2. CAPA (the Central Administration for Pharmaceutical Affairs) obligated Egydrug to ban distribution
of Avastin on Ophthalmology Hospitals.
References:
1.
2.
Avastin - Summary of Product Characteristics (SPC) - (EMEA) (Click here)
Avastin Label-(FDA) (Click here)
Case Report from Alexandria-Inflammatory hepatitis and raised liver
enzymes with Depo-Provera
The regional center in Alexandria has received an
ICSR concerning a female who was administered
Depo-Provera as a treatment for vaginal bleeding.
Three days later, the patient developed
inflammatory hepatitis with increased liver
enzymes; SGOT and SGPT levels reached 600 U/
L and 900 U/L respectively. The patient has
undergone tests for Hepatitis virus A, B and C, but
they were all negative. The patient is on liver
support as a treatment for the case but not
recovered yet. The patient didn't suffer previously
from any liver disease.
Depo-Provera injectable suspension contains 150
mg/ml medroxyprogesterone acetate (which is a
derivative of progesterone). It is a long-term
contraceptive agent, which gives 12 weeks
continuous contraception with each injection. It
may also be used for short-term contraception in
some cases.
Labeled information:
According to Depo-Provera Summary of Product
Characteristics (SmPC) it was stated under section
(4.8 Undesirable effects), that the following
adverse events were reported:
"Hepatobiliary disorders: abnormal liver enzymes,
jaundice (uncommon), disturbed liver function (not
Part I EPVC
Page 4
Volume 7, Issue 03
known)."
It was also stated under section (4.2 Posology and method of administration) that:
"The effect of hepatic disease on the pharmacokinetics of Depo-Provera is unknown. As Depo-Provera largely
undergoes hepatic elimination it may be poorly metabolised in patients with severe liver insufficiency."
The results of certain laboratory tests may be affected by the use of Depo-Provera:
Decreased
Increased
Gonadotrophin levels
Plasma progesterone levels
Urinary pregnanediol levels
Thyroid function tests (T3 uptake levels)
Glucose tolerance test
Metyrapone test
Liver function tests
Thyroid function tests (protein bound iodine
levels)
Coagulation test values for prothrombin
(Factor II), and Factors VII, VIII, IX and X
Plasma oestrogen levels
Plasma cortisol levels
Recommendations for Healthcare Professionals:

Depo-Provera is contraindicated in patients with the presence or history of severe hepatic disease,
whose liver function tests have not returned to normal.

Medroxyprogesterone is extensively metabolized in the liver. Most products are contraindicated in
patients with hepatic impairment. If needed for the palliative treatment metastatic endometrial
carcinoma, monitor closely; withhold or discontinue treatment if liver dysfunction develops and do
not resume until hepatic function has returned to normal.

Whether administered alone or in combination with estrogen, Depo-Provera should not be
employed in patients with abnormal uterine bleeding until a definite diagnosis has been
established and the possibility of genital tract malignancy eliminated.

Depo-Provera is contraindicated as a contraceptive in known or suspected hormone-dependent
malignancy of breast or genital organs.

History or emergence of the following conditions requires careful consideration and appropriate
investigation: migraine or unusually severe headaches, acute visual disturbances of any kind,
pathological changes in liver function and hormone levels.

In women with significant lifestyle and/or medical risk factors for osteoporosis, other methods of
contraception should be considered prior to use of Depo-Provera.

Before administration of Depo-Provera, liver enzymes test should be done.
References:
1. Emc-Depo-Provera, SmPC (Click here)
2. Drugs.com- Depo-Provera, SmPC (Click here)
Page 5
Part I EPVC
Volume 7, Issue 03
Case Reports from Sohag associated with RIVO
The Egyptian pharmaceutical Vigilance regional center in sohag had
received two ICSRs about Rivo tablets.
First ICSR: An infant male patient, 4 years old, was administered Rivo
75 mg for Slight fever from a long time as a solution once daily orally as
necessary. Then he suffered from vomiting blood, so the drug had been
withdrawn and the reaction was recovered.
Second ICSR: At 01/12/2015, an 11- years old female patient was
administrated Rivo 320 mg three times daily. Then, at 02/12/2015 she
suffered from bleeding from her nose so the drug has been withdrawn
and she had administrated adrenaline to recover the reaction.
Rivo (Acetyl Salicylic acid): A widely used analgesic, antipyretic, and anti-inflammatory agent; also
used as an antiplatelet agent.
Upon search , it was found that:
Avoid Rivo in patients with active peptic ulcer disease.

Rivo may cause gastric ulceration and bleeding.

Safety and effectiveness in pediatric patients have not been established. When given to children
aspirin may cause Reye’s syndrome.

Reye’s syndrome: is a rare and serious disease that damages the brain and the liver. There is an
association between Reye's syndrome and Aspirin used by fever caused by viral infections in children.

For this reason, aspirin should not be given to children aged less than 16 years.
References:
1.
FDA Aspirin label (Click here)
2.
emc Aspirin 300 leaflet (Click here)
3.
emc Aspirin 75 patient information leaflet (Click here)
Recall from the Egyptian market due to counterfeit
The department of Pharmacies & Warehouse Inspection at CAPA has decided to recall the following
products due to counterfeit:
1. Augmentin ES600 batch number 152044 with production date 05/2015 and Expiry date 01/2017,
where the original product is manufactured by MUP for GlaxsoSmithKline.
The counterfeited products can be differentiated from the authorized products as follows:
Part I EPVC
Page 6
Volume 7, Issue 03
Authorized packages
Counterfeited Packages
The Outer package:
 The word “Extra” is written on one side
of the package correctly.
 The Manufacture date, Expiry date,
batch number and price are imprinted on
the outer side of the upper lid.
The Bottle:
 The Manufacture date, Expiry date,
batch number and price are imprinted on
the label by an ink jet printer.
 The word “Extra” is written on the label
correctly.
The Outer package:
 The word “Extra is written incorrectly as
“Extia”.
 The Manufacture date, Expiry date,
batch number and price are imprinted on
the inner side of the upper lid.
The Bottle:
 The Manufacture date, Expiry date,
batch number and price are written on
the label as a part of it.
 The word “Extra is written incorrectly as
“Extia”.
2. Augmentin 457mg syrup batch number 152044 with production date 05/2015 and Expiry date
01/2017, where the original product is manufactured by MUP for GlaxsoSmithKline.
The counterfeited products can be differentiated from the authorized products as follows:
Authorized packages
The Outer package:
The Manufacture date, Expiry date, batch
number and price are imprinted on the outer
side of the upper lid.
Counterfeited Packages
The Outer package:
The Manufacture date, Expiry date, batch
number and price are imprinted on the inner
side of the upper lid.
The bottle:
 The Manufacture date, Expiry date,
batch number and price are imprinted on
the label by an ink jet printer.
 “Syrup in powder form” is printed on
the label.
The bottle:
 The Manufacture date, Expiry date,
batch number and price are written on
the label as a part of it.
 “Syrup in powder form” is not printed
on the label.
3. Lucentis 10mg/ml batch number S0059 with Expiry date 02/2017, the original product is
imported for Novartis Pharma.
The unauthorized product is illegally imported from Saudi Arabia, and can be differentiated
from the authorized ones as follows:
Authorized packages
 The importing company name is printed
on the outer package.
 The registration number is written.
 The price is stated by the Egyptian
pound
 Instructions are found on the package in
French and Spanish language.
Unauthorized Packages
 The importing company name is not
printed on the outer package.
 The registration number is not written.
 The price is not stated
 Arabic instructions are found on the
package.
Part I EPVC
Page 7
Volume 7, Issue 03
4. Allergan scientific office in Egypt, informed CAPA that it has discovered lots of counterfeited
product labeled as ‘COMBIGAN® eye drops’ that was circulated in Egypt. Allergan has identified
that the counterfeit bottles, actually contains different eye medications.
Allergan has determined that the counterfeit ‘COMBIGAN® ’ bottles carry the lot numbers ‘E74469’
or ‘E73028’, these lot numbers have never been shipped to Egypt, consequently the department of
Pharmacies & Warehouse Inspection has decided to recall those batches and its destruction.
“Batches” Recall of some pharmaceutical products from the Egyptian
market
The “Drug Factories Inspection Department” at the Central Administration of Pharmaceutical Affairs
(CAPA) has decided to recall Specific Batches of the following Pharmaceutical products:
Pharmaceutical Product
MAH
Batch numbers
Reason
Thiotacid 600mg
Eva Pharma
503458
Osipect Syrup
CID
08150258
Beco tablets
Misr Co.
Curam 642.9mg O/S
Novartis Pharma
(Manufactured by
Pharco)
131045
119075
118075
117075
400215
Non conformity of physical
properties
Non conformity of physical
properties
Non conformity of chemical
analysis
Non conformity of physical
properties
This decision was circulated to the Manufacturers, Marketing Authorization Holders (MAH) and
Distributers for these products to discontinue distribution of stocks of and recall the amount sold of
these batches ONLY from pharmacies.
Necessary measures would be taken against the violators.
NORCB Newsletter
February 2016
National Organization
for Research &
Control of Biologicals
Post Marketing
Surveillance and
Adverse Event
Following
immunization
Department
Inside this issue:
Influenza vaccine may
decrease atrial fibrillation
risks
1
study detects method to
stop HIV’s spread
1
Study shows flu vaccine's
effectiveness varies for
pregnant women
2
WHO renews commitment
to eliminating polio
2
Researchers have isolated human monoclonal
antibodies that target
multiple strains of Ebola
3
Synthetic vaccine test
shows immune response
to Zika virus
3
Volume 7 , Issue 2
Influenza vaccine may decrease atrial fibrillation risks
A new vaccine for influenza may be
able to decrease the chances of developing new-onset atrial fibrillation (AF),
which is an irregular or rapid heartbeat
that can be related to influenza. Scientists conducted the study to determine
when an influenza infection is considered a risk factor for the heart condition
and to evaluate whether the influenza
vaccine could decrease the chances of
developing atrial fibrillation. This heart
condition is the most common kind of
cardiac arrhythmia. Many clinics attribute most of their hemodynamic abnormalities, frequent hospitalizations and
blood clots to atrial fibrillation. Experts
have stated that there is a five-fold larger
risk of having a stroke with atrial fibrillation. Although the precise mechanisms of AF are not well understood,
accumulating evidence indicates that
inflammation and the autonomic nervous system are involved in the development of AF. The study, which involved
57,000 people, showed that people who
had not received their influenza vaccines had an 18 percent higher chance
of developing atrial fibrillation. According to the findings presented here,
the possibility of AF should be kept in
mind when patients with influenza infection complain of palpitations or experience ischemic stroke. Influenza
vaccinations should be encouraged for
patients, especially those who have a
high risk of atrial fibrillation, to try to
prevent the occurrence of atrial fibrillation and subsequent stroke.
Reference
Vaccine News Daily: (Click Here)
Study detects method to stop HIV’s spread
Researchers have detected a new way
to use RNA-based drug 5-aza-C to
stop HIV infections from spreading
throughout the body. The drug can be
altered to DNA before it makes its
way into the virus, as it initiates lethal
mutagenesis. This is a process where
HIV evolves at such a rapid speed that
the virus runs itself into exhaustion. 5aza-C stops HIV from spreading by
changing into 5-aza-deoxyC, the DNA
form of the drug. This enables the
drug to filter into the virus and ceases
the replication process from RNA to
DNA. The mechanism for how 5-aza-
C blocks HIV's infectivity through hypermutation. This discovery is important
because RNA drugs do not cost as much
as other treatments. This may help to
make HIV medications and treatments
more affordable for people who have
HIV. More than half of the world's HIV
population is concentrated in subSaharan Africa where there is very limited access to HIV drugs and treatment.
Reference
Vaccine News Daily: (Click Here)
Page 2
Part II NORCB
Volume 7, Issue 2
Study shows flu vaccine's effectiveness varies for pregnant women
Scientists recently conducted a study that
demonstrates that pregnant women have different T-follicular helper (Thf) cell expansion
according to their trimester, which affects the
effectiveness of the influenza vaccine. Officials
at the Centers for Disease Control and Prevention (CDC) recommend that the influenza vaccine be administered to all pregnant women
who have not received vaccinations within the
last year. The officials maintain their recommendations no matter the trimester of the
pregnant women. The study involved 36 pregnant women throughout the 2012 and 2014 flu
seasons. The women received inactivated in-
fluenza vaccines. The researchers collected blood
samples before the vaccination and 14 days afterward, showing the Thf cell response was different
depending on the trimester of the pregnancy. The scientists discovered that the vaccine’s impact on the
Thf cells is more significant during a pregnant women’s first trimester. The study results suggest that immunological changes during pregnancy may affect
the response to the vaccination,Future studies will
lead to a better understanding of vaccine immunology and how pregnant women respond to antigen exposure through the course of their pregnancy.
Reference
Vaccine News Daily: (Click here)
WHO renews commitment to eliminating polio
The World Health Organization (WHO) recently renewed its commitment and reviewed
its process in eliminating polio. There are 10
weeks until health professionals around the
world change from a trivalent polio vaccine to
a bivalent oral polio vaccine. This globally synchronized change is a significant milestone as
health professionals move forward for a world
without polio. At the meeting, the attendees
discussed how Africa has gone for four months
without detecting any wild or circulating poliovirus cases derived from vaccines. This is a
first in history, and it is also the first time that
there have not been any environmental positive
samples in the area for four months. In the last
week of January, there were no new wild poliovirus type 1 (WPV1) cases confirmed in Afghanistan. The last patient to contract the virus
had paralysis onset starting on Nov.19. The
cumulative number of cases for last year stands
at 19; there were 28 cases confirmed in 2014.In
Pakistan, there was one new WPV1 case con-
firmed in the last week of January. The patient’s paralysis began on Dec. 31. For last year, the country
has reported 54 cases. In 2014, there were 306 cases
confirmed. In Central Africa, there have not been
any new WPV1 cases confirmed in the last week or
for 2015. In 2014, health officials detected 10 cases.
Health professionals intend to continue taking proactive measures to eliminate polio from the world
health scene.
Reference
Vaccine News Daily: (Click here)
Page 3
Part II NORCB
Volume 7, Issue 2
Researchers have isolated human monoclonal antibodies that target
multiple strains of Ebola
Over the last few years, there has been a surge of
research to understand Ebola and develop medicines to stop it. And now researchers have isolated antibodies from Ebola survivors which
they say can neutralize multiple species of the
virus. The ebolavirus has claimed the lives of
more than 11,000 people in West Africa in the
past two years and although some countries are
marking the end of the recent Ebola epidemic-the World Health Organization (WHO) also
warns about the potential reemergence of the
virus in 2016.Monoclonal antibodies are the
product of a clone from a type of white blood
cell, scaled quickly by fusing it to a cancer cell to
grow it in relevant amounts for clinical use. The
researchers isolated these from Ebola patients
that have resisted the virus. In this study, a remarkably diverse array of virus-specific antibodies was isolated, which appeared to bind to various parts of the envelope protein of the virus.
Using these monoclonal antibodies may prove an
effective way to provide short-term protection to
healthcare workers and those that are at risk of being exposed to the virus. They may also be used as
antiviral drugs to treat patients who are already infected with the ebolavirus. Commenting on previous research which has developed and reengineered mouse antibodies which has limitations,
Crowe said: "This work points the way to using fully human antibodies as the next generation of antibody therapeutics
Reference:
Vaccine News Daily: (Click here)
Synthetic vaccine test shows immune response to Zika virus
A Company recently stated that its pre-clinical
testing for the company’s synthetic vaccine designed to protect people from the Zika virus has
shown a robust, durable immune response in test
subjects. This demonstrates that there is significant evidence that supports a vaccine to protect
people from the Zika virus. There have been serious autoimmune and neurological complications
that are related to Zika virus. These complications include microcephaly in newborns and
Guillain-Barre syndrome. The study used constructs from DNA vaccines to target several antigens of the Zika virus. These antigens were synthetically created then delivered into the subjects
with Cellectra electroporation delivery technolo-
gy. With robust antibody and killer T cell responses
generated by the vaccine in mice, the next step will
be testing the vaccine in non-human primates and
initiate clinical product manufacturing. The plan is
to initiate phase I human testing of Zika vaccine
before the end of 2016.
Reference:
Vaccine News Daily: (Click here)
What is Pharmacovigilance
According to the WHO, Pharmacovigilance is
A call for reporting
the science and activities relating to the de-
Please remember that you can report suspected adverse
tection, assessment, understanding and pre-
reaction of medicines to EPVC, and adverse reaction
vention of adverse effects or any other medicine-related problem.
following immunization to NORCB using the following communication information
What is the Egyptian Pharmaceutical Vigilance Center
With the increasing demand for patient's
safety which is becoming more stringent, the
Communications information
regulatory authorities are facing an increased demand for patient welfare and
Central Administration of Pharmaceutical Affairs
safety. Thus, The Egyptian Pharmaceutical
Egyptian Pharmaceutical Vigilance Center
Vigilance Center (EPVC) is constructed within
Pharmacovigilance Department
The Central Administration of Pharmaceutical Affairs (CAPA) Ministry of Health to be
21 Abd El Aziz Al Soud Street. El-Manial, Cairo, Egypt, PO Box: 11451
Phone: +202 – 23684288,
responsible for the collection and evaluation
Fax: +202 – 23610497
of information on pharmaceutical products
Email: pv.center@eda.mohealth.gov.eg
marketed in Egypt with particular reference
to adverse reactions. Furthermore, EPVC is
taking all appropriate measures to:
1.Encourage physicians and other healthcare
www.epvc.gov.eg
professionals to report the suspected adverse reactions to EPVC.
2.Necessitate the pharmaceutical companies to systematically collect information
on risks related to their medical products
National Organization for Research & Control of Biologicals
and to transmit them to EPVC.
Post Marketing Surveillance and Adverse Event Following
3.Provide information to end-users through
immunization Department
adverse drug reaction news bulletins, drug
51 Wezaret El Zeraa Street, Agouza, Giza P.O. Box: 354 Dokki
alerts and seminars.
Phone: +202 – 37 480 478
Fax: +202 – 37480472
Email: pmsdep@yahoo.com
ext. 118