‫לרופא‬
‫בעלון לרופא‬
‫בטיחות) בעלון‬
)‫מידע בטיחות‬
‫החמרה (( מידע‬
‫על החמרה‬
‫הודעה על‬
‫הודעה‬
___________3023 ,‫ אפריל‬32__ ‫תאריך‬
Foscavir :‫שם תכשיר באנגלית‬
8206260660 ‫מספר רישום‬
____________‫ליברה בע"מ‬-‫פארם‬-‫או‬-‫שם בעל הרישום__טק‬
‫ים‬/‫ים המבוקש‬/‫פרטים על השינוי‬
‫טקסט חדש‬
‫טקסט נוכחי‬
Foscavir is indicated for induction Foscavir is indicated for induction
and maintenance therapy of
and maintenance therapy of
cytomegalovirus (CMV) retinitis in cytomegalovirus (CMV) retinitis in
patients with AIDS. Induction therapy
patients with AIDS. Induction
of mucocutaneous Herpes Simplex therapy of mucocutaneous Herpes
Virus (HSV) infections, unresponsive
Simplex Virus (HSV) infections,
to acyclovir immunocompromised unresponsive to acyclovir
patients.
immunocompromised patients.
Following induction therapy
over 2-3 weeks Foscavir
produced stabilisation of retinal
lesions in approximately 80% of
cases treated. However, since
CMV causes latent infections
and since Foscavir exerts a
virustatic activity, relapses are
likely in the majority of patients
with persistent
immunodeficiency once
treatment is discontinued.
Following completion of
induction therapy, maintenance
therapy should be instituted with
a once daily regimen at an initial
dose of 60 mg/kg increasing to
90-120 mg/kg if tolerated. A
number of patients have received
90 mg/kg over a two hour period
as a maintenance therapy starting
dose. Maintenance therapy has
produced a delay in time to
retinitis progression. In patients
experiencing progression of
retinitis while receiving
maintenance therapy or off
Following induction therapy
over 2-3 weeks Foscavir
produced stabilisation of retinal
lesions in approximately 80%
of cases treated. However, since
CMV causes latent infections
and since Foscavir exerts a
virustatic activity, relapses are
likely in the majority of patients Therapeutic
with persistent
Indications
immunodeficiency once
treatment is discontinued.
Following completion of
induction therapy, maintenance
therapy should be instituted
with a once daily regimen at an
initial dose of 60 mg/kg
increasing to 90-120 mg/kg if
tolerated. A number of patients
have received 90 mg/kg over a
two hour period as a
maintenance therapy starting
dose. Maintenance therapy has
produced a delay in time to
retinitis progression. In patients
experiencing progression of
retinitis while receiving
‫פרק בעלון‬
therapy, reinstitution of
induction therapy has shown
equal efficacy equivalent to that
of the initial course.
Foscavir is also indicated for the
treatment of mucocutaneous
HSV infections, clinically
unresponsive to acyclovir in
immunocompromised patients.
The safety and efficacy of
Foscavir for the treatment of
other HSV infection (e.g.
retinitis, encephalitis);
congenital or neonatal disease;
or HSV in immunocompetent
individuals has not been
established.
The diagnosis of acyclovir
unresponsiveness can be made
either clinically by treatment
with intravenous acyclovir (510mg/kg t.i.d) for 10 days
without response or by in vitro
testing.
For treatment of acyclovir
unresponsive mucocutaneous
infections Foscavir was
administered at 40mg/kg every 8
hours over 2-3 weeks or until
healing. In a prospective
randomised study in patients
with AIDS, Foscavir treated
patients healed within 11-25
days, had a complete relief of
pain within 9 days and stopped
shedding HSV virus within 7
days.
Foscavir is not recommended for
treatment of CMV infections
other than retinitis or HSV or for
use in non-AIDS or nonimmunocompromised patients.
Since Foscavir can impair renal
maintenance therapy or off
therapy, reinstitution of
induction therapy has shown
equal efficacy equivalent to that
of the initial course.
Foscavir is also indicated for
the treatment of mucocutaneous
HSV infections, clinically
unresponsive to acyclovir in
immunocompromised patients.
The safety and efficacy of
Foscavir for the treatment of
other HSV infection (e.g.
retinitis, encephalitis);
congenital or neonatal disease;
or HSV in immunocompetent
individuals has not been
established.
The diagnosis of acyclovir
unresponsiveness can be made
either clinically by treatment
with intravenous acyclovir (510mg/kg t.i.d) for 10 days
without response or by in vitro
testing.
For treatment of acyclovir
unresponsive mucocutaneous
infections Foscavir was
administered at 40mg/kg every
8 hours over 2-3 weeks or until
healing. In a prospective
randomised study in patients
with AIDS, Foscavir treated
patients healed within 11-25
days, had a complete relief of
pain within 9 days and stopped
shedding HSV virus within 7
days.
Foscavir is not recommended
for treatment of CMV
infections other than retinitis or
HSV or for use in non-AIDS or
non-immunocompromised
patients.
Since Foscavir can impair renal
function, additive toxicity may occur
when used in combination with other
nephrotoxic drugs such as
Interaction with
other Medicinal
Products and other
function, additive toxicity may occur
when used in combination with other
nephrotoxic drugs such as
aminoglycoside antibiotics,
amphotericin B and cyclosporin A.
Moreover, since Foscavir can reduce
serum levels of ionised calcium,
extreme caution is advised when used
concurrently with other drugs known to
influence serum calcium levels, like i.v.
pentamidine. Renal impairment and
symptomatic hypocalcaemia
(Trousseau's and Chvostek's signs)
have been observed during concurrent
treatment with Foscavir and i.v.
pentamidine. Abnormal renal function
has been reported in connection with
the use of foscarnet in combination
with protease inhibitors associated with
impaired renal function e.g. ritonavir
and saquinavir.
The elimination of Foscavir may be
impaired by drugs which inhibit renal
tubular secretion.
There is no evidence of an increased
myelotoxicity when foscarnet is used in
combination with zidovudine (AZT).
Neither is there any pharmacokinetic
interaction between the two drugs.
There is no pharmacokinetic interaction
with ganciclovir, didanosine (ddI) or
zalcitabine (ddC).
The majority of patients who receive
Foscavir are severely immunocompromised and suffering from
serious viral infections. Patients’
physical status, the severity of the
underlying disease, other infections and
concurrent therapies contribute to
adverse events observed during use of
Foscavir.
The following undesirable effects have
been observed and reported during
treatment with Foscavir with the
following frequencies:
Very common (≥1/10), common
(≥1/100 to <1/10), uncommon
(≥1/1,000 to <1/100), rare (≥1/10,000
to <1/1,000), very rare (<1/10,000)
Clinical trial experience
The adverse events and frequencies
shown in Table 2 are based on the
foscarnet primary clinical trial
database. This includes adverse
experiences reported at any time during
induction, maintenance or follow-up
treatment in 5 clinical trials involving
188 patients with CMV retinitis.
aminoglycoside antibiotics,
amphotericin B and cyclosporin A.
Moreover, since Foscavir can reduce
serum levels of ionised calcium,
extreme caution is advised when used
concurrently with other drugs known
to influence serum calcium levels, like
i.v. pentamidine. Renal impairment
and symptomatic hypocalcaemia
(Trousseau's and Chvostek's signs)
have been observed during concurrent
treatment with Foscavir and i.v.
pentamidine. Abnormal renal function
has been reported in connection with
the use of foscarnet in combination
with protease inhibitors associated
with impaired renal function e.g.
ritonavir and saquinavir.
Forms of
Interaction
The elimination of Foscavir may be
impaired by drugs which inhibit renal
tubular secretion.
There is no evidence of an increased
myelotoxicity when foscarnet is used
in combination with zidovudine
(AZT). Neither is there any
pharmacokinetic interaction between
the two drugs.
In different patient populations
Foscavir has been administered to
more than 11,500 patients, the
majority severely
immunocompromised and suffering
from serious viral infections.
The patient's physical status, the
severity of the underlying disease,
other infections and concurrent
therapy also contribute to the
observed adverse event profile of
Foscavir.
Consistent findings associated with
Foscavir administration are renal
function impairment, impact on serum
electrolytes and haemoglobin
concentration, convulsions and local
genital irritation/ulceration.
The adverse events discussed and
tabulated below refer to results for
188 AIDS patients in prospective
clinical trials and include those events
related, unrelated and of unknown
relationship to Foscavir, The adverse
Undesirable
Effects1
Adverse events are presented by
event profile from the market is
frequency and body System-Organ
similar to that reported in clinical
Class (SOC). In these clinical trials,
studies.
hydration and attention to electrolyte
balance was not consistently given; the Renal function impairment: Twentyfrequency of some adverse events will
seven percent of the above 188 study
be lower when current
patients experienced renal functional
recommendations are followed (see
impairment recorded as a rise in
‘Posology and method of
serum creatinine (19%), decreases in
administration’ and ‘Special warnings
creatinine clearance (6%), abnormal
and special precautions for use’).
renal function (9%), acute renal
Table 2 Frequency of adverse events failure (2%), uraemia (1%) and
from the primary clinical trial database polyuria in 2%. Metabolic acidosis
was seen in 1%. The overall pattern of
SOC
Frequency Event
these symptoms is consistent with
Blood and
Very
Granulocytop previous experiences although the
lymphatic
Common
enia
incidence may vary. Most patients
system
(≥10%)
with increased serum creatinine have
disorders
shown normalisation or return to preCommon
Leukopenia,
treatment levels within 1-10 weeks of
(≥1% and
Thrombocyto
treatment discontinuation.
<10%)
penia
Metabolis
m and
nutrition
disorders
Very
Common
(≥10%)
Common
(≥1% and
<10%)
Nervous
system
disorders
Uncommon
(≥0.1% and
<1%)
Very
Common
(≥10%)
Common
(≥1% and
<10%)
Gastrointes
tinal
disorders
Very
Common
(≥10%)
Common
(≥1% and
<10%)
Skin and
subcutaneo
us
disorders
Very
Common
(≥10%)
Anorexia,
Hypokalaemi
a,
Hypomagnesa
emia,
Hypocalcaemi
a
Hyperphosph
ataemia,
Hyponatraemi
a,
Hypophospha
taemia, Blood
alkaline
phosphatase
increased,
Blood lactate
dehydrogenas
e increased
Acidosisb
Dizziness,
Headache,
Paraesthesia
Coordination
abnormal,
Convulsion,
Hypoaesthesi
a, Muscle
contractions
involuntary,
Neuropathy,
Tremor
Diarrhoea,
Nausea,
Vomiting
Abdominal
pain,
Constipation,
Dyspepsia
Rash
Electrolytes: Among the above 188
patients, hypocalcaemia was recorded
in 14%. Also, hypomagnesaemia was
recorded in 15%. Frequently recorded
were also hypokalemia in 16% and
hvpophosphataemia and
hyperphosphataemia in 8 and 6%
respectively. Foscarnet chelates with
metal ions (Ca2+ Mg2+, Fe2+, Zn2+) and
acute hypocalcaemia, sometimes
symptomatic, has been a common
observation in some 30% of AIDS
patients receiving foscarnet.
Experimental and clinical data have
shown that foscarnet acutely decreases
ionised calcium in a dose-related
manner. The drop in serum calcium is
reversible. It is reasonable to assume
that the infusion rate significantly
affects the decrease rate of ionised
calcium.
Convulsions: Among the AIDS
patients referred to above, convulsions
including grand mal were recorded in
10%, Based on the occurrence of
convulsions among
immunocompromised patients
receiving foscarnet, an association
between foscarnet induced
hypocalcaemia or a direct action of
foscarnet per se and convulsions has
been discussed. Although many of the
patients experiencing convulsions had
pre-existing CNS abnormalities such
as cryptococcal meningitis, space
occupying lesions or other CNS
tumours, an association with foscarnet
can not be excluded.
General
disorders
and
administrat
ion site
conditions
Investigati
ons
Very
Common
(≥10%)
Asthenia,
Chills,
Fatigue,
Pyrexia
Common
(≥1% and
<10%)
Very
Common
(≥10%)
Malaise,
Oedema
Common
(≥1% and
<10%)
Immune
system
disorders
Psychiatric
disorders
Cardiac
disorders
Vascular
disorders
Hepatobiliary
disorders
Reproducti
ve system
and breast
disorders
Renal and
urinary
disorders
a
Common
(≥1% and
<10%)
Common
(≥1% and
<10%)
Common
(≥1% and
<10%)
Common
(≥1% and
<10%)
Common
(≥1% and
<10%)
Common
(≥1% and
<10%)
Common
(≥1% and
<10%)
Blood
creatinine
increased,
Haemoglobin
decreased
Creatinine
renal
clearance
decreased,
Electrocardio
gram
abnormala
Sepsis
Aggression,
Agitation,
Anxiety,
Confusional
state,
Depression,
Nervousness
Palpitations
Haemoglobin concentration:
Decreases of the haemoglobin
concentration have been observed in
25-33% of patients. Generally, there
has been no consistent pattern of
simultaneous decreases in white blood
cell and platelet counts. Some 30% of
the above study patients were also on
concurrent AZT treatment. Many
AIDS patients were anaemic already
before foscarnet administration.
Local irritation in terms of
thrombophlebitis in peripheral veins
following infusion of undiluted
foscarnet solution and genital
irritation/ulcerations have been
observed. Since foscarnet is excreted
in high concentrations in the urine
local irritation/ulceration may ensue
especially during induction therapy
when high doses of foscarnet are
being administered.
Other Adverse Events: Other adverse
events that were recorded in the 188
study patients include a variety of
symptoms varying in frequency from
1% to approximately 60%, the latter
being the incidence for fever.
Subgrouped by body system the
Hypertension, following adverse events, related,
Hypotension, unrelated or of unknown relationship
Thrombophle to foscarnet therapy were recorded.
bitis
Hepatic
function
abnormal,
Gammaglutamyltrans
ferase
increased,
Alanine
aminotransfer
ase increased,
Aspartate
aminotransfer
ase increased
Genital
irritation and
ulceration
Renal
impairment,
Renal failure
acute,
Dysuria,
Polyuria
This frequency is based on 2 reports
of electrocardiogram abnormal from
188 patients in the primary clinical trial
database; the post-marketing reporting
rate is ‘Very rare’.
b
This frequency is based on 1 report of
acidosis from 188 patients in the
Body as a whole: Asthenia, fatigue,
malaise and chills were observed in
12, 20, 7 and 13% respectively and
sepsis in 7%.
Gastro-intestinal system disorders:
Nausea and vomiting were observed
in 45 and 25% respectively and
diarrhoea in 32%. Abdominal pain
and occasionally dyspepsia and
constipation were observed in 10, 3
and 6% respectively. Isolated cases of
pancreatitis have been reported from
marketed use.
Metabolic and nutritional
disorders: Hyponatremia and oedema
in legs were seen in 4 and 1%
respectively and increase in LDH and
alkaline phosphatases in 2 and 3%
respectively. Increased levels of
amylase have been reported from
marketed use.
Central/Peripheral nervous system
disorders: Paraesthesia was observed
in 18%, headache in 25% and
primary clinical trial database; the postmarketing reporting rate is ‘Rare’.
Post-marketing and other experience
Reporting rates for events detected in
studies other than those in the primary
clinical trial database and/or from
spontaneous post-marketing reports are
shown in Table 3.
Table 3 Reporting rates for events
detected in other clinical studies or
from spontaneous post-marketing
reports
a
SOC
Renal and
urinary
disorders
Blood and
lymphatic
system
disorders
Endocrine
disorders
Gastrointes
tinal
disorders
Skin and
subcutaneo
us
disorders
Musculosk
eletal
disorders
Investigati
ons
Frequency
Common
(≥1% and
<10%)
Unknown
Event
Renal paina
Unknown
Unknown
Diabetes
insipidus
Pancreatitis
Unknown
Pruritus
Cardiac
disorders
Unknown
Musculosk
eletal
disorders
Unknown
Investigati
ons
Unknown
Neutropenia
Unknown
Myalgia
Unknown
Blood
amylase
increased
Electrocardio
gram QT
prolongedb,
Ventricular
arrhythmia
Muscular
weakness,
Myopathy,
Myositis,
Rhabdomyoly
sis
Blood
creatine
phosphokinas
e increased
This reporting rate is based on 7
reports of renal pain from two
prospective clinical trials involving 107
patients (trials 90FP48 and 91FP49).
There were no reports in the primary
clinical trial database; the postmarketing reporting rate is ‘Very rare’.
b
This reporting rate is based on 3
spontaneous reports of QT prolongation
from 80000 patients.
dizziness in 12%. Involuntary muscle
contractions and tremor were seen in 9
and 5% respectively. Hypoaesthesia,
ataxia and neuropathy were observed
in 7, 4 and 6% respectively.
Psychiatric disorders: Anorexia,
anxiety and nervousness were
observed in 15 and 5% respectively
and depression in 10%, confusion in
7%, psychosis in 1%, agitation in 3%
and aggressive reaction in 2%.
White blood cells: Adverse events
related to white blood cells included
leukopenia 9%, granulocytopenia
17%. In these patients over 90% had
some degree of leukopenia already
before foscarnet administration, in 8%
severe or even life-threatening.
Moreover in some patients, it is
noteworthy that mean WBC counts
increased during treatment with
foscarnet. Although a few patients
worsened in this respect, there is no
clear evidence to indicate that
foscarnet is myelosuppressive.
Platelet, bleeding, clotting
disorders: Thrombocytopenia was
observed in 4%.
Skin and appendages: Rash was
observed in 16%.
Liver and biliary system disorders:
Abnormal liver function was observed
in 4% and increase in serum ALAT
and ASAT in 3 and 2% respectively
and gamma GT in 2%.
Cardiovascular disorders: Abnormal
ECG, hypertension and hypotension
were observed in 1, 4 and 2%
respectively.
Heart rate and rhythm disorders:
Ventricular arrhythmia has been
reported in 2 patients from marketed
use.
Urinary system disorders: A few
cases of diabetes insipidus, usually of
the nephrogenic type, have been
reported from marketed use.
Musculo-skeletal disorders: Muscle
weakness has been reported from
marketed use.
Overdose symptoms,
Overdose symptoms,
emergency procedures, emergency
Overdose
antidotes
procedures, antidotes
Overdose has been reported during the
use of Foscavir in 33 patients, the
highest dose being some 20 about 10
times the recommended prescribed
dose. Some of the cases were relative
overdoses, in that the dose of drug used
had not been promptly adjusted for a
patient experiencing reduced renal
function. There are cases where it has
been reported that no clinical sequelae
were consequent on the overdose. 28 of
the patients experienced adverse events
and 5 patients suffered no ill effects in
connection with foscarnet overdosing.
4 patients died, one from
respiratory/cardiac arrest 3 days after
stopping foscarnet, one from
progressive AIDS and renal failure
approximately 2 months after the last
foscarnet dose, one from end stage
AIDS and bacteraemia 2 weeks after
overdosing and one from multi-organ
failure 11 days after stop of foscarnet.
The pattern of adverse events reported
in association connection with an
overdose of Foscavir was is in
accordance correspondence with the
known adverse event profile of the drug
symptoms previously observed during
foscarnet therapy.
Foscarnet is not compatible with
dextrose 30% solution,
amphotericin B, acyclovir
sodium, ganciclovir,
pentamidine isethionate,
trimethoprim-sulfamtoxazole
and vancomycin hydrochloride.
Neither is foscarnet compatible
with solutions containing
calcium. It is recommended that
other drugs should not be
infused concomitantly in the
same line. until further
experience is gained.
1
Overdose has been reported during the
use of Foscavir, the highest dose
being some 20 times the
recommended dose. Some of the cases
were relative
overdoses, in that the dose of drug
used had not been promptly adjusted
for
a patient experiencing reduced renal
function.
There are cases where it has been
reported that no clinical sequelae were
consequent on the overdose.
The pattern of adverse events reported
in association with an overdose of
Foscavir is in accordance with the
known adverse event profile of the
drug.
Haemodialysis increases Foscavir
elimination and may be of benefit in
relevant cases.
Foscarnet is not compatible
with dextrose 30% solution,
amphotericin B, acyclovir
sodium, ganciclovir,
pentamidine isethionate,
trimethoprim-sulfamtoxazole
and vancomycin hydrochloride.
Neither is foscarnet compatible Incompatibilities
with solutions containing
calcium. It is recommended that
other drugs should not be
infused concomitantly in the
same line, until further
experience is gained.
:‫הערות‬
the section "Undesirable Effects" was rewritten in the manufacturer's format
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