ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
IntronA 3 million IU/0.5 ml solution for injection or infusion
2.
One vial of solution for injection or infusion contains 3 million IU of recombinant interferon alfa-2b
produced in
E.coli
by recombinant DNA technology, in 0.5 ml of solution.
For a full list of excipients, see section 6.1.
3.
Solution for injection or infusion.
Clear and colourless solution.
4.
Chronic hepatitis B
Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral
replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg),
elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or
fibrosis.
Chronic hepatitis C
Before initiating treatment with IntronA, consideration should be given to the results from clinical
trials comparing IntronA with pegylated interferon (see section 5.1).
Adult patients
IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated
transaminases without liver decompensation and who are positive for hepatitis C virus RNA (HCV-
RNA) (see section 4.4).
The best way to use IntronA in this indication is in combination with ribavirin.
Chidren 3 years of age and older and adolescents
IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years of
age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver
decompensation, and who are positive for HCV-RNA.
When deciding not to defer treatment until adulthood, it is important to consider that the combination
therapy induced a growth inhibition. The reversibility of growth inhibition is uncertain
The decision to treat should be made on a case by case basis (see section 4.4).
Hairy cell leukaemia
Treatment of patients with hairy cell leukaemia.
Chronic myelogenous leukaemia
Monotherapy
Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic
myelogenous leukaemia.
2
Clinical experience indicates that a haematological and cytogenetic major/minor response is obtainable
in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ leukaemic
cells in the bone marrow, whereas a minor response is ≥ 34 %, but < 90 % Ph+ cells in the marrow.
Combination therapy
The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months
of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses
and to significantly prolong the overall survival at three years when compared to interferon alfa-2b
monotherapy.
Multiple myeloma
As maintenance therapy in patients who have achieved objective remission (more than 50 % reduction
in myeloma protein) following initial induction chemotherapy.
Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the
plateau phase; however, effects on overall survival have not been conclusively demonstrated.
Follicular lymphoma
Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction
chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of
the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm),
systemic symptoms (weight loss > 10 %, pyrexia > 38°C for more than 8 days, or nocturnal sweats),
splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or
epidural involvement, serous effusion, or leukaemia.
Carcinoid tumour
Treatment of carcinoid tumours with lymph node or liver metastases and with "carcinoid syndrome".
Malignant melanoma
As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic
recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.
Treatment must be initiated by a physician experienced in the management of the disease.
Not all dose forms and strengths are appropriate for some indications. Appropriate dose form and
strength must be selected.
If adverse events develop during the course of treatment with IntronA for any indication, modify the
dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent
intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment
with IntronA. At the discretion of the physician, the patient may self-administer the dose for
maintenance dose regimens administered subcutaneously.
Chronic hepatitis B
The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a
week (every other day) for a period of 4 to 6 months.
The administered dose should be reduced by 50 % in case of occurrence of haematological disorders
(white blood cells < 1,500/mm
3
, granulocytes < 1,000/mm
3
, thrombocytes < 100,000/mm
3
). Treatment
should be discontinued in case of severe leukopaenia (< 1,200/mm
3
), severe neutropaenia (< 750/mm
3
)
or severe thrombocytopaenia (< 70,000/mm
3
).
For all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment
(at the maximum tolerated dose), discontinue IntronA therapy.
Chronic hepatitis C
3
Adults
IntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day)
to adult patients, whether administered as monotherapy or in combination with ribavirin.
Children 3 years of age or older and adolescents
IntronA 3 MIU/m
2
is administered subcutaneously 3 times a week (every other day) in combination
with ribavirin capsules or oral solution administered orally in two divided doses daily with food
(morning and evening).
(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for
combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see
ribavirin oral solution SPC).
Relapse patients (adults)
IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are
available for 6 months of treatment, it is recommended that patients be treated with IntronA in
combination with ribavirin for 6 months.
Naïve patients (adults)
The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be
given alone mainly in case of intolerance or contraindication to ribavirin.
- IntronA in combination with ribavirin
Based on the results of clinical trials, in which data are available for 12 months of treatment, it is
recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.
Treatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who
exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment
sample) and high pre-treatment viral load.
Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into
account in order to extend therapy to 12 months.
During clinical trials, patients who failed to show a virologic response after 6 months of treatment
(HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV-
RNA below lower limit of detection six months after withdrawal of treatment).
- IntronA alone
The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of
between 12 and 18 months is advised.
It is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point
HCV-RNA status should be determined. Treatment should be continued in patients who exhibit
negative HCV-RNA.
Naïve patients (children and adolescents)
The efficacy and safety of IntronA in combination with ribavirin has been studied in children and
adolescents who have not been previously treated for chronic hepatitis C.
Duration of treatment for children and adolescents
•
Genotype 1:
The recommended duration of treatment is one year. Patients who fail to achieve
virological response at 12 weeks are highly unlikely to become sustained virological
responders (negative predictive value 96 %). Therefore, it is recommended that children and
adolescent patients receiving IntronA/ribavirin combination be discontinued from therapy if
their week 12 HCV-RNA dropped < 2 log
10
compared to pretreatment, or if they have
detectable HCV-RNA at treatment week 24.
•
Genotype 2/3
: The recommended duration of treatment is 24 weeks.
4
Hairy cell leukaemia
The recommended dose is 2 million IU/m
2
administered subcutaneously three times a week (every
other day) for both splenectomised and non-splenectomised patients. For most patients with Hairy Cell
Leukaemia, normalisation of one or more haematological variables occurs within one to two months of
IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet
count and haemoglobin level) may require six months or more. This regimen must be maintained
unless the disease progresses rapidly or severe intolerance is manifested.
Chronic myelogenous leukaemia
The recommended dose of IntronA is 4 to 5 million IU/m
2
administered daily subcutaneously. Some
patients have been shown to benefit from IntronA 5 million IU/m
2
administered daily subcutaneously
in association with cytarabine (Ara-C) 20 mg/m
2
administered daily subcutaneously for 10 days per
month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled,
administer the maximum tolerated dose of IntronA (4 to 5 million IU/m
2
daily) to maintain
haematological remission.
IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial
haematological remission or a clinically meaningful cytoreduction has not been achieved.
Multiple myeloma
Maintenance therapy
In patients who are in the plateau phase (more than 50 % reduction of myeloma protein) following
initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy,
subcutaneously, at a dose of 3 million IU/m
2
three times a week (every other day).
Follicular lymphoma
Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of
5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens
are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide,
doxorubicin, teniposide and prednisolone).
Carcinoid tumour
The usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week
(every other day). Patients with advanced disease may require a daily dose of 5 million IU. The
treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long
as the patient responds to interferon alfa-2b treatment.
Malignant melanoma
As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m
2
daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to
sodium chloride 9 mg/ml (0.9 %) solution for injection and administered as a 20-minute infusion (see
section
6.6). As maintenance treatment, the recommended dose is 10 million IU/m
2
administered
subcutaneously three days a week (every other day) for 48 weeks.
If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes
decrease to < 500/mm
3
or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to
> 5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates.
Interferon alfa-2b treatment is to be restarted at 50 % of the previous dose. If intolerance persists after
dose adjustment or if granulocytes decrease to < 250/mm
3
or ALT/AST rises to > 10 x upper limit of
normal, discontinue interferon alfa-2b therapy.
Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at
the recommended dose, with dose reduction for toxicity as described.
IntronA may be administered using either glass or plastic disposable injection syringes.
5
-
Hypersensitivity to the active substance or to any of the excipients.
-
A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure,
recent myocardial infarction, severe arrhythmic disorders.
-
Severe renal or hepatic dysfunction; including that caused by metastases.
-
Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).
-
Chronic hepatitis with decompensated cirrhosis of the liver.
-
Chronic hepatitis in patients who are being or have been treated recently with
immunosuppressive agents excluding short term corticosteroid withdrawal.
-
Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant
recipients.
-
Pre-existing thyroid disease unless it can be controlled with conventional treatment.
Children and adolescents
-
Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal
ideation or suicide attempt.
Combination therapy with ribavirin
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with
chronic hepatitis C.
Psychiatric and central nervous system (CNS)
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been
observed in some patients during IntronA therapy, and even after treatment discontinuation mainly
during the 6-month follow-up period. Among children and adolescents treated with IntronA in
combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult
patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult
patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, emotional
lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes directed against
others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status
have been observed with alpha interferons. Patients should be closely monitored for any signs or
symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these
undesirable effects must be borne in mind by the prescribing physician and the need for adequate
therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal
ideation is identified, it is recommended that treatment with IntronA be discontinued, and the patient
followed, with psychiatric intervention as appropriate.
Patients with existence of or history of severe psychiatric conditions
If treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severe
psychiatric conditions, this should only be initiated after having ensured appropriate individualised
diagnostic and therapeutic management of the psychiatric condition.
The use of interferon alfa-2b in children and adolescents with existence of or history of severe psychiatric
conditions is contraindicated (see section 4.3).
Children and adolescent population: Growth and development (chronic hepatitis C)
During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to
48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see
sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy
with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile
decrease in height percentile as compared to baseline) in 21 % of children despite being off treatment
for more than 5 years.
Case by case benefit/risk assessment in children
6
The expected benefit of treatment should be carefully weighed against the safety findings observed for
children and adolescents in the clinical trials (see sections 4.8 and 5.1).
-
It is important to consider that the combination therapy induced a growth inhibition, the
reversibility of which is uncertain.
-
This risk should be weighed against the disease characteristics of the child, such as evidence
of disease progression (notably fibrosis), co-morbidities that may negatively influence the
disease progression (such as HIV co-infection), as well as prognostic factors of response, (HCV
genotype and viral load).
Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the
risk of growth inhibition. There are no data on long term effects on sexual maturation.
Hypersensitivity reactions
Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to
interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops,
discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate
interruption of treatment.
Adverse experiences including prolongation of coagulation markers and liver abnormalities
Moderate to severe adverse experiences may require modification of the patient's dose regimen, or in
some cases, termination of IntronA therapy.
Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of
coagulation markers which might indicate liver decomposition.
Any patient developing liver function abnormalities during treatment with IntronA must be monitored
closely and treatment discontinued if signs and symptoms progress.
Hypotension
Hypotension may occur during IntronA therapy or up to two days post-therapy and may require
supportive treatment.
Need for adequate hydration
Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotension
related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.
Pyrexia
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon
therapy, other causes of persistent pyrexia must be ruled out.
Patients with debilitating medical conditions
IntronA must be used cautiously in patients with debilitating medical conditions, such as those with a
history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone
to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g.,
thrombophlebitis, pulmonary embolism) or severe myelosuppression.
Pulmonary conditions
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been
observed rarely in interferon alpha treated patients, including those treated with IntronA. The
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto,
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Any
patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray
taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function
impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha.
While this has been reported more often in patients with chronic hepatitis C treated with interferon
alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha.
Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to
be associated with resolution of pulmonary adverse events.
7
Ocular adverse events
Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, and retinal
artery or vein obstruction have been reported in rare instances after treatment with alpha interferons.
All patients should have a baseline eye examination. Any patient complaining of changes in visual
acuity or visual fields, or reporting other ophthalmologic symptoms during treatment with IntronA,
must have a prompt and complete eye examination. Periodic visual examinations during IntronA
therapy are recommended particularly in patients with disorders that may be associated with
retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA should be
considered in patients who develop new or worsening ophthalmological disorders.
Obtundation, coma and encephalopathy
More significant obtundation and coma, including cases of encephalopathy, have been observed in
some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a
few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high
doses of IntronA.
Patients with pre-existing cardiac abnormalities
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or
current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is
recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced
stages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiac
arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require
discontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiac
disease.
Hypertriglyceridemia
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed.
Monitoring of lipid levels is, therefore, recommended.
Patients with psoriasis and sarcoidosis
Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of
IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies
the potential risk.
Kidney and liver graft rejection
Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of
kidney graft rejection. Liver graft rejection has also been reported.
Auto-antibodies and autoimmune disorders
The development of auto-antibodies and autoimmune disorders has been reported during treatment
with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at
increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be
evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also
section
4.4 Chronic hepatitis C, Monotherapy
(thyroid abnormalities) and section
4.8).
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic
hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting
the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment
should be withdrawn and corticosteroid therapy discussed (see section 4.8).
Concomitant chemotherapy
Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C,
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and
duration), which may be life-threatening or fatal as a result of the concomitantly administered
medicinal product. The most commonly reported potentially life-threatening or fatal adverse events
include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of
the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the
8
concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the
frequency and severity of cutaneous vasculitis may be increased.
Chronic hepatitis C
Combination therapy with ribavirin
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with
chronic hepatitis C.
All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases
(i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation.
Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to
commencing treatment.
Monotherapy
Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid
abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy,
2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by
conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid
status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C,
evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that
time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can
be maintained in the normal range by medication. Determine TSH levels if, during the course of
IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the
presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained
in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid
dysfunction occurring during treatment (also see Children and adolescents, Thyroid monitoring).
Thyroid supplemental monitoring specific for children and adolescents
Approximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapy
developed increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decrease
below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated
and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA
therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid
dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid
abnormalities are detected, the patient’s thyroid status should be evaluated and treated as clinically
appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid
dysfunction (e.g. TSH).
HCV/HIV Coinfection
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at
increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to
HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy
and zidovudine could be at increased risk of developing anaemia.
Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic
decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin
may increase the risk in this patient subset.
Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients
receiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging
effect on teeth and mucous membranes of the mouth during long-term treatment with the combination
of IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular
dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they
should be advised to rinse out their mouth thoroughly afterwards.
Laboratory Tests
9
Standard haematological tests and blood chemistries (complete blood count and differential, platelet
count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be
conducted in all patients prior to and periodically during systemic treatment with IntronA.
During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16,
and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to
greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and
symptoms of liver failure are observed. During ALT flare, the following liver function tests must be
monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.
In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and
differential must be monitored weekly during the induction phase of therapy and monthly during the
maintenance phase of therapy.
Effect on fertility
Interferon may impair fertility (see section
4.6 and section
5.3).
Important information about some of the ingredients of IntronA
This medicinal product contains less than 1 mmol sodium (23 mg) per 0.5 ml, i.e., essentially
"sodium-free".
Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with
IntronA.
Interactions between IntronA and other medicinal products have not been fully evaluated. Caution
must be exercised when administering IntronA in combination with other potentially
myelosuppressive agents.
Interferons may affect the oxidative metabolic process. This must be considered during concomitant
therapy with medicinal products metabolised by this route, such as the xanthine derivatives
theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline
levels must be monitored and dose adjusted if necessary.
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been
observed rarely in interferon alpha treated patients, including those treated with IntronA. The
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto,
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).
Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C,
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and
duration) (see section 4.4).
(Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with
chronic hepatitis C).
Women of childbearing potential/contraception in males and females
Women of childbearing potential have to use effective contraception during treatment. Decreased
serum estradiol and progesterone concentrations have been reported in women treated with human
leukocyte interferon.
IntronA must be used with caution in fertile men.
Combination therapy with ribavirin
10
Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be
taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in
combination with ribavirin. Females of childbearing potential and their partners must each use an
effective contraceptive during treatment and for 4 months after treatment has been concluded. Male
patients and their female partners must each use an effective contraceptive during treatment and for 7
months after treatment has been concluded (see ribavirin SPC).
Pregnancy
There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA
is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Combination therapy with ribavirin
Ribavirin therapy is contraindicated in women who are pregnant.
Breast-feeding
It is not known whether the components of this medicinal product are excreted in human milk.
Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior
to initiation of treatment.
Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment
with IntronA, and therefore it is recommended that they avoid driving or operating machinery.
See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in
combination with ribavirin in patients with chronic hepatitis C.
In clinical trials conducted in a broad range of indications and at a wide range of doses (from
6 MIU/m
2
/week in hairy cell leukaemia up to 100 MIU/m
2
/week in melanoma), the most commonly
reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were
often reversible within 72 hours of interruption or cessation of treatment.
Adults
In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in
combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three
times a week. In
Table 1
the frequency of patients reporting (treatment related) undesirable effects is
presented from clinical trials in naïve patients treated for one year. Severity was generally mild to
moderate. The adverse reactions listed in
Table 1
are based on experience from clinical trials and post-
marketing. Within the organ system classes, adverse reactions are listed under headings of frequency
using the following categories: very common (≥1/10); common (≥1/100 to <1/10);
uncommon
(≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known. Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1.
Adverse reactions reported during clinical trials or following the marketing use of IntronA alone
or in combination with ribavirin
System Organ Class
Adverse Reactions
Infections and infestations
Very common:
Common:
Uncommon:
Rarely:
Pharyngitis*, infection viral*
Bronchitis, sinusitis, herpes simplex (resistance), rhinitis
Bacterial infection
Pneumonia
§
, sepsis
Blood and lymphatic system disorders
Very common:
Leukopaenia
11
Common:
Very rarely:
Not known
:
Thrombocytopaenia, lymphadenopathy, lymphopenia
Aplastic anaemia
Pure red cell aplasia, idiopathic thrombocytopenic purpura,
thrombotic thrombocytopenic purpura
Immune system disorders
§
Very rarely:
Not known:
Sarcoidosis, exacerbation of sarcoidosis
Systemic lupus erythematosus, vasculitis, rheumatoid
arthritis (new or aggravated), Vogt-Koyanagi-Harada
syndrome, acute hypersensitivity reactions including
urticaria, angioedema, bronchoconstriction, anaphylaxis
§
Endocrine disorders
Common:
Very rarely:
Hypothyroidism
§
, hyperthyroidism
§
Diabetes, aggravated diabetes
Metabolism and nutrition disorders
Very common:
Common:
Very rarely:
Anorexia
Hypocalcaemia, dehydration, hyperuricemia, thirst
Hyperglycaemia, hypertriglyceridaemia
§
, increased appetite
Psychiatric disorders
§
Very common:
Depression, insomnia, anxiety, emotional lability*,
agitation, nervousness
Confusion, sleep disorder, libido decreased
Suicide ideation
Suicide, suicide attempts, aggressive behaviour (sometimes
directed against others), psychosis including hallucinations
Homicidal ideation, mental status change
§
, mania, bipolar
disorders
Common:
Rarely:
Very rarely:
Not known:
Nervous system disorders
§
Very common:
Common:
Dizziness, headache, concentration impaired, mouth dry
Tremor, paresthesia, hypoesthesia, migraine, flushing,
somnolence, taste perversion
Peripheral neuropathy
Cerebrovascular haemorrhage, cerbrovascular ischaemia,
seizure, impaired consciousness, encephalopathy
Mononeuropathies, coma
§
Uncommon:
Very rarely:
Not known:
Eye disorders
Very common:
Common:
Vision blurred
Conjunctivitis, vision abnormal, lacrimal gland disorder, eye
pain
Retinal haemorrhages
§
, retinopathies (including macular
oedema), retinal artery or vein obstruction
§
, optic neuritis,
papilloedema, loss of visual acuity or visual field, cotton-
wool spots
§
Rarely:
Ear and labyrinth
Common:
Very rarely:
Vertigo, tinnitus
Hearing loss, hearing disorder
Cardiac disorders
Common:
Rarely:
Very rarely:
Not known:
Palpitation, tachycardia
Cardiomyopathy
Myocardial infarction, cardiac ischaemia
Congestive heart failure, pericardial effusion, arrhythmia
Vascular disorders
Common:
Very rarely:
Hypertension
Peripheral ischaemia, hypotension
§
Respiratory, thoracic and mediastinal
disorders
Very common:
Dyspnoea*, coughing*
12
Common:
Epistaxis, respiratory disorder, nasal congestion, rhinorrhea,
cough nonproductive
Pulmonary infiltrates
§
, pneumonitis
§
Very rarely:
Gastrointestinal disorders
Very common:
Nausea/vomiting, abdominal pain, diarrhoea, stomatitis,
dyspepsia
Stomatitis ulcerative, right upper quadrant pain, glossitis,
gingivitis, constipation, loose stools
Pancreatitis, ischaemic colitis, ulcerative colitis, gingival
bleeding
Periodontal disorder NOS, dental disorder NOS
§
Common:
Very rarely:
Not known:
Hepatobiliary disorders
Common:
Very rarely:
Hepatomegaly
Hepatotoxicity, (including fatality)
Skin and subcutaneous tissue disorders
Very common:
Common:
Alopecia, pruritus*, skin dry*, rash*, sweating increased
Psoriasis (new or aggravated)
§
, rash maculopapular, rash
erythematous, eczema, erythema, skin disorder
Stevens Johnson syndrome, toxic epidermal necrolysis,
erythema multiforme
Very rarely:
Musculoskeletal and connective tissue
disorders
Very common:
Common:
Very rarely:
Myalgia, arthralgia, musculoskeletal pain
Arthritis
Rhabdomyolysis, myositis, leg cramps, back pain
Renal and urinary disorders
Common:
Very rarely:
Micturition frequency
Renal failure, renal insufficiency, nephrotic syndrome
Reproductive system and breast
disorders
Common:
Amenorrhea, breast pain, dysmenorrhea, menorrhagia,
menstrual disorder, vaginal disorder
General disorders and administration
site conditions
Very common:
Injection site inflammation, injection site reaction*, fatigue,
rigors, pyrexia
§
, flu-like symptoms
§
, asthenia, irritability,
chest pain, malaise
Injection site pain
Injection site necrosis, face oedema
Common:
Very rarely:
Investigations
Very common:
Weight decrease
*These events were only common with IntronA alone
§
See section 4.4
These undesirable effects have also been reported with IntronA alone.
The undesirable effects seen with hepatitis C are representative of those reported when IntronA
is
administered in other indications, with some anticipated dose-related increases in incidence. For
example, in a trial of high-dose adjuvant IntronA
treatment in patients with melanoma, incidences of
fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-
like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C
trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of
patients, respectively), in comparison with the mild to moderate severity usually associated with lower
13
Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with
pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy,
that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients
without prior evidence of cardiac disease (see section 4.4).
A wide variety of autoimmune and immune-mediated disorders have been reported with alpha
interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or
aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including
mononeuropathies (see also section
4.4).
Clinically significant laboratory abnormalities, most frequently occurring at doses greater than
10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in
haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and
serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase
in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis
subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.
Children and adolescent population
Chronic Hepatitis C - Combination therapy with ribavirin
In clinical trials of 118 children and adolescents (3 to 16 years of age), 6 % discontinued therapy due
to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent
population studied was similar to that observed in adults, although there is a paediatric- specific
concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of
9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during
treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of
44
th
percentile, which was below the median of the normative population and less than their mean
baseline height (48
th
percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height
percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from
the start of treatment to the end of long-term follow-up (up to 5 years). During combination therapy
for up to 48 weeks with IntronA and ribavirin, growth inhibition is observed, the reversibility of which
is uncertain. In particular, decrease in mean height percentile from baseline to the end of the long-term
follow-up was most prominent in prepubertal age children (see section 4.4).
Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients
(2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult
patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression,
emotional lability, and somnolence) (see
section 4.4). In addition, injection site disorders, pyrexia,
anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents
compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for
anaemia and neutropaenia.
The adverse reactions listed in
Table 2
are based on experience from the two multicentre children and
adolescent clinical trials. Within the organ system classes, adverse reactions are listed under headings
of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 2
Adverse reactions very commonly and commonly reported during clinical trials inchildren
and adolescent patients treated with IntronA in combination with ribavirin
System Organ Class
Adverse Reactions
Infection and infestations
Very common:
Common:
Viral infection, pharyngitis
Fungal infection, bacterial infection, pulmonary infection, otitis
media, tooth abscess, herpes simplex, urinary tract infection,
vaginitis, gastroenteritis
Neoplasms benign, malignant
14
and unspecified (including
cysts and polyps)
Common:
Neoplasm (unspecified)
Blood and lymphatic system
disorders
Very common:
Common:
Anaemia, neutropaenia
Thrombocytopaenia, lymphadenopathy
Endocrine disorders
Very common:
Common:
Hypothyroidism
§
,
Hyperthyroidism
§
, virilism
Metabolism and nutrition
disorders
Very common:
Common:
Anorexia
Hypertriglyceridemia
§
, hyperuricemia, increased appetite
Psychiatric disorders
§
Very common:
Common:
Depression, emotional lability, insomnia
Suicidal ideation, aggressive reaction, confusion, behaviour
disorder, agitation, somnambulism, anxiety, nervousness, sleep
disorder, abnormal dreaming, apathy
Nervous system disorders
§
Very common:
Common:
Headache, dizziness
Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia,
hyperaesthesia, concentration impaired, somnolence
Eye disorders
Common:
Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Vascular disorders
Common:
Flushing, pallor
Respiratory, thoracic and
mediastinal disorders
Common:
Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal
irritation, rhinorrhea, sneezing
Gastrointestinal disorders
Very common:
Common:
Diarrhoea, vomiting, nausea, abdominal pain
Mouth ulceration, stomatitis ulcerative, stomatitis, right upper
quadrant pain, dyspepsia, glossitis, gastroesophogeal reflux, rectal
disorder, gastrointestinal disorder, constipation, loose stools,
toothache, tooth disorder
Hepatobiliary disorders
Common:
Hepatic function abnormal
Skin and subcutaneous tissue
disorders
Very common:
Common:
Alopecia, rash
Photosensitivity reaction, maculopapular rash, eczema, acne, skin
disorder, nail disorder, skin discolouration, pruritus, dry skin,
erythema, bruise, sweating increased
Musculoskeletal and
connective tissue disorders
Very common:
Arthralgia, myalgia, musculoskeletal pain
Renal and urinary disorders
Common:
Enuresis, micturition disorder, urinary incontinence
Reproductive system and
breast disorders
Common:
Female
: amenorrhea, menorrhagia, menstrual disorder, vaginal
disorder
Male:
testicular pain
General disorders and
15
administration site
conditions
Very common:
Injection site inflammation, injection site reaction, fatigue, rigors,
pyrexia
§
, influenza-like symptoms
§
, malaise, irritability
Chest pain, asthenia, oedema, injection site pain
Common:
Investigations
Very common:
Growth rate decrease (height and/or weight decrease for age)
§
Injury and poisoning
Common:
§
See section 4.4
Skin laceration
No case of overdose has been reported that has led to acute clinical manifestations. However, as for
any pharmacologically active compound, symptomatic treatment with frequent monitoring of vital
signs and close observation of the patient is indicated.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: interferon alfa-2b, ATC code: L03A B05
IntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant
DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of
approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically
engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.
The activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b
protein corresponding to 2.6 x l0
8
IU. International Units are determined by comparison of the activity
of the recombinant interferon alfa-2b with the activity of the international reference preparation of
human leukocyte interferon established by the World Health Organisation.
The interferons are a family of small protein molecules with molecular weights of approximately
15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or
various synthetic and biological inducers. Three major classes of interferons have been identified:
alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain
several different molecular species of interferon. More than 14 genetically distinct human alpha
interferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.
Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface.
Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly
asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species
specificity. Studies with other interferons have demonstrated species specificity. However, certain
monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure
to human type 1 interferons.
The results of several studies suggest that, once bound to the cell membrane, interferon initiates a
complex sequence of intracellular events that include the induction of certain enzymes. It is thought
that this process, at least in part, is responsible for the various cellular responses to interferon,
including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and
such immunomodulating activities as enhancement of the phagocytic activity of macrophages and
augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities
may contribute to interferon's therapeutic effects.
16
Recombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing both
animal and human cell culture systems as well as human tumour xenografts in animals. It has
demonstrated significant immunomodulatory activity
in vitro
.
Recombinant interferon alfa-2b also inhibits viral replication
in vitro
and
in vivo
. Although the exact
antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell
metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are
unable to leave the cell.
Chronic hepatitis B
Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates
that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been
observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity
and mortality has been observed.
Interferon alfa-2b (6 MIU/m
2
3 times a week for 6 months) has been given to children with chronic
active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover
children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of
depression were observed.
Chronic hepatitis C in adult patients
In adult patients receiving interferon in combination with ribavirin, the achieved sustained response
rate is 47 %. Superior efficacy has been demonstrated with the combination of pegylated interferon
with ribavirin (sustained response rate of 61 % achieved in a study performed in naïve patients with a
ribavirin dose > 10.6 mg/kg, p < 0.01).
IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical
trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of
IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologic
response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C
confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/ml), a liver
biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic
hepatitis, and abnormal serum ALT.
IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with
ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were
followed for an additional 6 months after the end of treatment for the determination of sustained
virologic response. Sustained virologic response rates for treatment groups treated for one year with
IntronA alone or in combination with ribavirin (from two studies) are shown in
Table 3
.
Co-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold for
the treatment of chronic heptatitis C in naïve patients. HCV genotype and baseline virus load are
prognostic factors which are known to affect response rates. The increased response rate to the
combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The
relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most
difficult to treat subgroup of patients (genotype 1 and high virus load) (
Table 3
).
Response rates in these trials were increased with compliance. Regardless of genotype, patients who
received IntronA in combination with ribavirin and received ≥ 80 % of their treatment had a higher
sustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment
(56 % vs. 32 % in trial C/I98-580).
Table 3
Sustained virologic response rates with IntronA + ribavirin (one year of
treatment) by genotype and viral load
17
HCV Genotype
I
N=503
C95-132/I95-143
I/R
N=505
C95-132/I95-143
I/R
N=505
C/I98-580
All Genotypes
16 %
41 %
47 %
Genotype 1
9 %
29 %
33 %
Genotype 1
≤ 2 million
copies/ml
25 %
33 %
45 %
Genotype 1
> 2 million
copies/ml
3 %
27 %
29 %
Genotype 2/3
31 %
65 %
79 %
I
IntronA (3 MIU 3 times a week)
I/R
IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)
HCV/HIV Co-infected patients
Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies,
patients who received IntronA plus ribavirin, were less likely to respond than patients who received
pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is
presented in
Table 4.
Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which
enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with
HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plus
ribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a
follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled
95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV.
Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 µg /week based on
weight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (3 MIU TIW) plus ribavirin
(800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period
of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml
(Amplicor) who were treated for 24 weeks with a 6-month follow-up period.
Table 4
Sustained virological response based on genotype after IntronA in combination with
ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in
HCV/HIV co-infected patients
Study 1
1
Study 2
2
pegylated
interferon
alfa-2b
(1.5 µg/kg/
week) +
ribavirin
(800 mg)
IntronA
(3 MIU TIW) +
ribavirin
(800 mg)
p
value
a
pegylated
interferon
alfa-2b (100
or
150
c
µg/week)
+ ribavirin
(800-
1,200 mg)
d
IntronA
(3 MIU TIW)
+ ribavirin
(800-
1,200 mg)
d
p
value
b
All
27 % (56/205) 20 % (41/205) 0.047 44 % (23/52)
21 % (9/43)
0.017
Genotype 1,
4
17 % (21/125)
6 % (8/129)
0.006 38 % (12/32)
7 % (2/27)
0.007
Genotype 2,
3
44 % (35/80)
43 % (33/76)
0.88 53 % (10/19)
47 % (7/15)
0.730
MIU = million international units; TIW = three times a week.
18
a: p value based on Cochran-Mantel Haenszel Chi square test.
b: p value based on chi-square test.
c: subjects < 75 kg received 100 µg/week pegylated interferon alfa-2b and subjects ≥ 75 kg received 150 µg/week
pegylated interferon alfa-2b.
d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.
1
Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.
2
Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.
Relapse patients
A total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronA
monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA
increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic
hepatitis C (48.6 % vs. 4.7 %). This enhancement in efficacy included loss of serum HCV
(< 100 copies/ml by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was
sustained when measured 6 months after the end of treatment.
Long-Term efficacy data
In a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-
2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic
response and assess the impact of continued viral negativity on clinical outcomes. 462 patients
completed at least 5 years of long-term follow-up and only 12 sustained responders' out of
492 relapsed during this study.
The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with
a 95 % Confidence Interval of
[95 %, 99 %].
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (with or without ribavirin)
results in long-term clearance of the virus providing resolution of the hepatic infection and clinical
'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients
with cirrhosis (including hepatocarcinoma).
Chronic hepatitis C in children and adolescent population
Three clinical trials have been conducted in children and adolescents; two with standard interferon and
ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin
were less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.
Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable
HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in
two multicentre trials and received IntronA 3 MIU/m
2
3 times a week plus ribavirin 15 mg/kg per day
for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 %
male, 80 % Caucasian, and 78 % genotype 1,64 % ≤ 12 years of age. The population enrolled mainly
consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained
virological response rates in children and adolescents were similar to those in adults. Due to the lack
of data in these two multicentre trials for children with severe progression of the disease, and the
potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b
needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).
Study results are summarized in
Table 5
.
Table 5.
Sustained virological response in previously untreated children and
adolescents
IntronA 3 MIU/m
2
3 times a week
+
ribavirin 15 mg/kg/day
Overall Response
a
(n=118)
54 (46 %)*
19
Genotype 1 (n=92)
33 (36 %)*
Genotype 2/3/4 (n=26)
21 (81 %)*
*Number (%) of patients
a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during
follow-up period
Long-term efficacy data
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C
patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all
enrolled subjects completed this study of which 75 % (42/56) were sustained
responders. The purpose
of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess
the impact of continued viral negativity on clinical outcomes for patients who were sustained
responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but
one of the paediatric subjects remained sustained virologic responders during long-term follow-up
after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for
continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients
treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at
follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with
cirrhosis (including hepatocarcinoma).
Results from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin
In a multicentre trial children and adolescents 3 to 17 years of age with compensated chronic
hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 μg/m
2
plus ribavirin
15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load.
All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received
treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and
63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate
hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential
for undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirin
needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs
section 4.4). The study results are summarized in
Table 6.
Table 6.
Sustained virological response rates (n
a,b
(%)) in previously untreated children
and adolescents by genotype and treatment duration – All subjects
n = 107
24 weeks
48 weeks
All Genotypes
26/27 (96 %)
44/80 (55 %)
Genotype 1
-
38/72 (53 %)
Genotype 2
14/15 (93 %)
-
12/12 (100 %) 2/3 (67 %)
Genotype 4 - 4/5 (80 %)
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of
detection=125 IU/ml.
b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.
c: Patients with genotype 3 low viral load (< 600,000 IU/ml) were to receive 24 weeks of treatment while
those with genotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment.
5.2 Pharmacokinetic properties
The pharmacokinetics of IntronA were studied in healthy volunteers following single 5 million IU/m
2
and 10 million IU doses administered subcutaneously, at 5 million IU/m
2
administered intramuscularly
20
Genotype 3
c
and as a 30-minute intravenous infusion. The mean serum interferon concentrations following
subcutaneous and intramuscular injections were comparable. C
max
occurred three to 12 hours after the
lower dose and six to eight hours after the higher dose. The elimination half-lives of interferon
injections were approximately two to three hours, and six to seven hours, respectively. Serum levels
were below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous and
intramuscular administration resulted in bioavailabilities greater than 100 %.
After intravenous administration, serum interferon levels peaked (135 to 273 IU/ml) by the end of the
infusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscular
administration of medicinal product, becoming undetectable four hours after the infusion. The
elimination half-life was approximately two hours.
Urine levels of interferon were below the detection limit following each of the three routes of
administration.
Interferon neutralising factor assays were performed on serum samples of patients who received
IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies
which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors
developing in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %.
The detectable titres are low in almost all cases and have not been regularly associated with loss of
response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was
observed apparently due to the low titres.
Children and adolescent population
Multiple-dose pharmacokinetic properties for IntronA injection and ribavirin capsules in children and
adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in
Table 7
. The
pharmacokinetics of IntronA and ribavirin (dose-normalized) are similar in adults and children or
adolescents.
21
Table 7.
Mean (% CV) multiple-dose pharmacokinetic parameters for IntronA and ribavirin
capsules when administered to children or adolescents with chronic hepatitis C
Parameter
Ribavirin
15 mg/kg/day as 2 divided
doses
(n = 17)
IntronA
3 MIU/m
2
3 times a week
(n = 54)
T
max
(hr)
1.9 (83)
5.9 (36)
C
max
(ng/ml)
3,275 (25)
51 (48)
AUC*
29,774 (26)
622 (48)
Apparent clearance l/hr/kg
0.27 (27)
Not done
*AUC
12
(ng.hr/ml) for ribavirin; AUC
0-24
(IU.hr/ml) for IntronA
5.3 Preclinical safety data
Although interferon is generally recognised as being species specific, toxicity studies in animals were
conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no
evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with
20 x 10
6
IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in
monkeys given 100 x 10
6
IU/kg/day for 3 months.
In studies of interferon use in non-human primates, abnormalities of the menstrual cycle have been
observed (see section 4.4).
Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic
in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in
offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in
Macaca
mulatta
(rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose
of 2 million IU/m
2
. Abortion was observed in all dose groups (7.5 million, 15 million and
30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups
(corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of
2 million IU/m
2
). High doses of other forms of interferons alpha and beta are known to produce dose-
related anovulatory and abortifacient effects in rhesus monkeys.
Mutagenicity studies with interferon alfa-2b revealed no adverse events.
IntronA plus ribavirin
No studies have been conducted in juvenile animals to examine the effects of treatment with interferon
alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results
have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with
ribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination with
ribavirin).
6.
6.1 List of excipients
Disodium phosphate anhydrous
Sodium dihydrogen phosphate monohydrate
Edetate disodium
Sodium chloride
M-cresol
Polysorbate 80
Water for injections
22
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
18 months.
Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25ºC for a period
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the product is not used during the seven-day period, it cannot be put back in the
refrigerator for a new storage period and must be discarded.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
For storage conditions of the medicinal product, see section 6.3.
6.5 Nature and contents of container
0.5 ml of solution (corresponding to 3 MIU) in a single dose vial (type I glass) with a stopper
(halobutyl rubber) in an flip-off seal (aluminium) with a bonnet (polypropylene).
Pack sizes of 1.
Or
0.5 ml of solution (corresponding to 3 MIU) in a single dose vial (type I glass) with a stopper
(halobutyl rubber) in an flip-off seal (aluminium) with a bonnet (polypropylene).
The pack size also contains 1 injection syringe, 1 injection needle and 1 cleansing swab.
Packs sizes of 1, 6 or 12.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Not all dose forms and strengths are appropriate for some indications. Please make sure to select an
appropriate dose form and strength.
IntronA solution for injection or infusion may be injected directly after withdrawal of the appropriate
doses from the vial with a sterile injection syringe.
Detailed instructions for the subcutaneous use of the product are provided with the package leaflet
(refer to “How to self inject IntronA”).
Preparation of IntronA for intravenous infusion: The infusion is to be prepared immediately prior to
use. Any size vial may be used to measure the required dose; however, final concentration of
interferon in sodium chloride solution must be not less than 0.3 million IU/ml. The appropriate dose of
IntronA is withdrawn from the vial(s), added to 50 ml of 9 mg/ml (0.9 %) sodium chloride solution for
injection in a PVC bag or glass bottle for intravenous use and administered over 20 minutes.
No other medicinal product can be infused concomitantly with IntronA.
As with all parenteral medicinal products, prior to administration inspect IntronA, solution for
injection or infusion, visually for particulate matter and discolouration. The solution should be clear
and colourless.
Any unused product must be discarded after withdrawal of the dose.
23
7.
SP Europe
73, rue de Stalle
B-1180 Bruxelles
Belgium
8.
EU/1/99/127/011
EU/1/99/127/012
EU/1/99/127/013
EU/1/99/127/014
9.
Date of first authorisation : 9 March 2000
Date of latest renewal :
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/
24
1.
IntronA 5 million IU/0.5 ml solution for injection or infusion
2.
One vial of solution for injection or infusion contains 5 million IU of recombinant interferon alfa-2b
produced in
E.coli
by recombinant DNA technology, in 0.5 ml of solution.
For a full list of excipients, see section 6.1.
3.
Solution for injection or infusion.
Clear and colourless solution.
4.
Chronic hepatitis B
Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral
replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg),
elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or
fibrosis.
Chronic hepatitis C
Before initiating treatment with IntronA, consideration should be given to the results from clinical
trials comparing IntronA with pegylated interferon (see section 5.1).
Adult patients
IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated
transaminases without liver decompensation and who are positive for hepatitis C virus RNA (HCV-
RNA) (see section 4.4).
The best way to use IntronA in this indication is in combination with ribavirin.
Chidren 3 years of age and older and adolescents
IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years of
age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver
decompensation, and who are positive for HCV-RNA.
When deciding not to defer treatment until adulthood, it is important to consider that the combination
therapy induced a growth inhibition. The reversibility of growth inhibition is uncertain
The decision to treat should be made on a case by case basis (see section 4.4).
Hairy cell leukaemia
Treatment of patients with hairy cell leukaemia.
Chronic myelogenous leukaemia
Monotherapy
Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic
myelogenous leukaemia.
25
Clinical experience indicates that a haematological and cytogenetic major/minor response is obtainable
in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ leukaemic
cells in the bone marrow, whereas a minor response is ≥ 34 %, but < 90 % Ph+ cells in the marrow.
Combination therapy
The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months
of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses
and to significantly prolong the overall survival at three years when compared to interferon alfa-2b
monotherapy.
Multiple myeloma
As maintenance therapy in patients who have achieved objective remission (more than 50 % reduction
in myeloma protein) following initial induction chemotherapy.
Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the
plateau phase; however, effects on overall survival have not been conclusively demonstrated.
Follicular lymphoma
Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction
chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of
the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm),
systemic symptoms (weight loss > 10 %, pyrexia > 38°C for more than 8 days, or nocturnal sweats),
splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or
epidural involvement, serous effusion, or leukaemia.
Carcinoid tumour
Treatment of carcinoid tumours with lymph node or liver metastases and with "carcinoid syndrome".
Malignant melanoma
As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic
recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.
Treatment must be initiated by a physician experienced in the management of the disease.
Not all dose forms and strengths are appropriate for some indications. Appropriate dose form and
strength must be selected.
If adverse events develop during the course of treatment with IntronA for any indication, modify the
dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent
intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment
with IntronA. At the discretion of the physician, the patient may self-administer the dose for
maintenance dose regimens administered subcutaneously.
Chronic hepatitis B
The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a
week (every other day) for a period of 4 to 6 months.
The administered dose should be reduced by 50 % in case of occurrence of haematological disorders
(white blood cells < 1,500/mm
3
, granulocytes < 1,000/mm
3
, thrombocytes < 100,000/mm
3
). Treatment
should be discontinued in case of severe leukopaenia (< 1,200/mm
3
), severe neutropaenia (< 750/mm
3
)
or severe thrombocytopaenia (< 70,000/mm
3
).
For all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment
(at the maximum tolerated dose), discontinue IntronA therapy.
Chronic hepatitis C
26
Adults
IntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day)
to adult patients, whether administered as monotherapy or in combination with ribavirin.
Children 3 years of age or older and adolescents
IntronA 3 MIU/m
2
is administered subcutaneously 3 times a week (every other day) in combination
with ribavirin capsules or oral solution administered orally in two divided doses daily with food
(morning and evening).
(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for
combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see
ribavirin oral solution SPC).
Relapse patients (adults)
IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are
available for 6 months of treatment, it is recommended that patients be treated with IntronA in
combination with ribavirin for 6 months.
Naïve patients (adults)
The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be
given alone mainly in case of intolerance or contraindication to ribavirin.
- IntronA in combination with ribavirin
Based on the results of clinical trials, in which data are available for 12 months of treatment, it is
recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.
Treatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who
exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment
sample) and high pre-treatment viral load.
Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into
account in order to extend therapy to 12 months.
During clinical trials, patients who failed to show a virologic response after 6 months of treatment
(HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV-
RNA below lower limit of detection six months after withdrawal of treatment).
- IntronA alone
The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of
between 12 and 18 months is advised.
It is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point
HCV-RNA status should be determined. Treatment should be continued in patients who exhibit
negative HCV-RNA.
Naïve patients (children and adolescents)
The efficacy and safety of IntronA in combination with ribavirin has been studied in children and
adolescents who have not been previously treated for chronic hepatitis C.
Duration of treatment for children and adolescents
•
Genotype 1:
The recommended duration of treatment is one year. Patients who fail to achieve
virological response at 12 weeks are highly unlikely to become sustained virological
responders (negative predictive value 96 %). Therefore, it is recommended that children and
adolescent patients receiving IntronA/ribavirin combination be discontinued from therapy if
their week 12 HCV-RNA dropped < 2 log
10
compared to pretreatment, or if they have
detectable HCV-RNA at treatment week 24.
•
Genotype 2/3
: The recommended duration of treatment is 24 weeks.
27
Hairy cell leukaemia
The recommended dose is 2 million IU/m
2
administered subcutaneously three times a week (every
other day) for both splenectomised and non-splenectomised patients. For most patients with Hairy Cell
Leukaemia, normalisation of one or more haematological variables occurs within one to two months of
IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet
count and haemoglobin level) may require six months or more. This regimen must be maintained
unless the disease progresses rapidly or severe intolerance is manifested.
Chronic myelogenous leukaemia
The recommended dose of IntronA is 4 to 5 million IU/m
2
administered daily subcutaneously. Some
patients have been shown to benefit from IntronA 5 million IU/m
2
administered daily subcutaneously
in association with cytarabine (Ara-C) 20 mg/m
2
administered daily subcutaneously for 10 days per
month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled,
administer the maximum tolerated dose of IntronA (4 to 5 million IU/m
2
daily) to maintain
haematological remission.
IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial
haematological remission or a clinically meaningful cytoreduction has not been achieved.
Multiple myeloma
Maintenance therapy
In patients who are in the plateau phase (more than 50 % reduction of myeloma protein) following
initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy,
subcutaneously, at a dose of 3 million IU/m
2
three times a week (every other day).
Follicular lymphoma
Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of
5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens
are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide,
doxorubicin, teniposide and prednisolone).
Carcinoid tumour
The usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week
(every other day). Patients with advanced disease may require a daily dose of 5 million IU. The
treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long
as the patient responds to interferon alfa-2b treatment.
Malignant melanoma
As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m
2
daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to
sodium chloride 9 mg/ml (0.9 %) solution for injection and administered as a 20-minute infusion (see
section
6.6). As maintenance treatment, the recommended dose is 10 million IU/m
2
administered
subcutaneously three days a week (every other day) for 48 weeks.
If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes
decrease to < 500/mm
3
or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to
> 5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates.
Interferon alfa-2b treatment is to be restarted at 50 % of the previous dose. If intolerance persists after
dose adjustment or if granulocytes decrease to < 250/mm
3
or ALT/AST rises to > 10 x upper limit of
normal, discontinue interferon alfa-2b therapy.
Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at
the recommended dose, with dose reduction for toxicity as described.
IntronA may be administered using either glass or plastic disposable injection syringes.
28
-
Hypersensitivity to the active substance or to any of the excipients.
-
A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure,
recent myocardial infarction, severe arrhythmic disorders.
-
Severe renal or hepatic dysfunction; including that caused by metastases.
-
Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).
-
Chronic hepatitis with decompensated cirrhosis of the liver.
-
Chronic hepatitis in patients who are being or have been treated recently with
immunosuppressive agents excluding short term corticosteroid withdrawal.
-
Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant
recipients.
-
Pre-existing thyroid disease unless it can be controlled with conventional treatment.
Children and adolescents
-
Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal
ideation or suicide attempt.
Combination therapy with ribavirin
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with
chronic hepatitis C.
Psychiatric and central nervous system (CNS)
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been
observed in some patients during IntronA therapy, and even after treatment discontinuation mainly
during the 6-month follow-up period. Among children and adolescents treated with IntronA in
combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult
patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult
patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, emotional
lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes directed against
others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status
have been observed with alpha interferons. Patients should be closely monitored for any signs or
symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these
undesirable effects must be borne in mind by the prescribing physician and the need for adequate
therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal
ideation is identified, it is recommended that treatment with IntronA be discontinued, and the patient
followed, with psychiatric intervention as appropriate.
Patients with existence of or history of severe psychiatric conditions
If treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severe
psychiatric conditions, this should only be initiated after having ensured appropriate individualised
diagnostic and therapeutic management of the psychiatric condition.
The use of interferon alfa-2b in children and adolescents with existence of or history of severe psychiatric
conditions is contraindicated (see section 4.3).
Children and adolescent population: Growth and development (chronic hepatitis C)
During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to
48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see
sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy
with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile
decrease in height percentile as compared to baseline) in 21 % of children despite being off treatment
for more than 5 years.
Case by case benefit/risk assessment in children
29
The expected benefit of treatment should be carefully weighed against the safety findings observed for
children and adolescents in the clinical trials (see sections 4.8 and 5.1).
-
It is important to consider that the combination therapy induced a growth inhibition, the
reversibility of which is uncertain.
-
This risk should be weighed against the disease characteristics of the child, such as evidence
of disease progression (notably fibrosis), co-morbidities that may negatively influence the
disease progression (such as HIV co-infection), as well as prognostic factors of response, (HCV
genotype and viral load).
Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the
risk of growth inhibition. There are no data on long term effects on sexual maturation.
Hypersensitivity reactions
Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to
interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops,
discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate
interruption of treatment.
Adverse experiences including prolongation of coagulation markers and liver abnormalities
Moderate to severe adverse experiences may require modification of the patient's dose regimen, or in
some cases, termination of IntronA therapy.
Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of
coagulation markers which might indicate liver decomposition.
Any patient developing liver function abnormalities during treatment with IntronA must be monitored
closely and treatment discontinued if signs and symptoms progress.
Hypotension
Hypotension may occur during IntronA therapy or up to two days post-therapy and may require
supportive treatment.
Need for adequate hydration
Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotension
related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.
Pyrexia
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon
therapy, other causes of persistent pyrexia must be ruled out.
Patients with debilitating medical conditions
IntronA must be used cautiously in patients with debilitating medical conditions, such as those with a
history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone
to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g.,
thrombophlebitis, pulmonary embolism) or severe myelosuppression.
Pulmonary conditions
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been
observed rarely in interferon alpha treated patients, including those treated with IntronA. The
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto,
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Any
patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray
taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function
impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha.
While this has been reported more often in patients with chronic hepatitis C treated with interferon
alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha.
Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to
be associated with resolution of pulmonary adverse events.
30
Ocular adverse events
Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, and retinal
artery or vein obstruction have been reported in rare instances after treatment with alpha interferons.
All patients should have a baseline eye examination. Any patient complaining of changes in visual
acuity or visual fields, or reporting other ophthalmologic symptoms during treatment with IntronA,
must have a prompt and complete eye examination. Periodic visual examinations during IntronA
therapy are recommended particularly in patients with disorders that may be associated with
retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA should be
considered in patients who develop new or worsening ophthalmological disorders.
Obtundation, coma and encephalopathy
More significant obtundation and coma, including cases of encephalopathy, have been observed in
some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a
few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high
doses of IntronA.
Patients with pre-existing cardiac abnormalities
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or
current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is
recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced
stages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiac
arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require
discontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiac
disease.
Hypertriglyceridemia
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed.
Monitoring of lipid levels is, therefore, recommended.
Patients with psoriasis and sarcoidosis
Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of
IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies
the potential risk.
Kidney and liver graft rejection
Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of
kidney graft rejection. Liver graft rejection has also been reported.
Auto-antibodies and autoimmune disorders
The development of auto-antibodies and autoimmune disorders has been reported during treatment
with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at
increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be
evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also
section
4.4 Chronic hepatitis C, Monotherapy
(thyroid abnormalities) and section
4.8).
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic
hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting
the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment
should be withdrawn and corticosteroid therapy discussed (see section 4.8).
Concomitant chemotherapy
Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C,
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and
duration), which may be life-threatening or fatal as a result of the concomitantly administered
medicinal product. The most commonly reported potentially life-threatening or fatal adverse events
include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of
the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the
31
concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the
frequency and severity of cutaneous vasculitis may be increased.
Chronic hepatitis C
Combination therapy with ribavirin
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with
chronic hepatitis C.
All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases
(i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation.
Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to
commencing treatment.
Monotherapy
Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid
abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy,
2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by
conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid
status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C,
evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that
time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can
be maintained in the normal range by medication. Determine TSH levels if, during the course of
IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the
presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained
in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid
dysfunction occurring during treatment (also see Children and adolescents, Thyroid monitoring).
Thyroid supplemental monitoring specific for children and adolescents
Approximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapy
developed increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decrease
below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated
and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA
therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid
dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid
abnormalities are detected, the patient’s thyroid status should be evaluated and treated as clinically
appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid
dysfunction (e.g. TSH).
HCV/HIV Coinfection
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at
increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to
HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy
and zidovudine could be at increased risk of developing anaemia.
Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic
decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin
may increase the risk in this patient subset.
Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients
receiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging
effect on teeth and mucous membranes of the mouth during long-term treatment with the combination
of IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular
dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they
should be advised to rinse out their mouth thoroughly afterwards.
Laboratory Tests
32
Standard haematological tests and blood chemistries (complete blood count and differential, platelet
count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be
conducted in all patients prior to and periodically during systemic treatment with IntronA.
During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16,
and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to
greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and
symptoms of liver failure are observed. During ALT flare, the following liver function tests must be
monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.
In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and
differential must be monitored weekly during the induction phase of therapy and monthly during the
maintenance phase of therapy.
Effect on fertility
Interferon may impair fertility (see section
4.6 and section
5.3).
Important information about some of the ingredients of IntronA
This medicinal product contains less than 1 mmol sodium (23 mg) per 0.5 ml, i.e., essentially
"sodium-free".
Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with
IntronA.
Interactions between IntronA and other medicinal products have not been fully evaluated. Caution
must be exercised when administering IntronA in combination with other potentially
myelosuppressive agents.
Interferons may affect the oxidative metabolic process. This must be considered during concomitant
therapy with medicinal products metabolised by this route, such as the xanthine derivatives
theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline
levels must be monitored and dose adjusted if necessary.
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been
observed rarely in interferon alpha treated patients, including those treated with IntronA. The
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto,
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).
Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C,
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and
duration) (see section 4.4).
(Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with
chronic hepatitis C).
Women of childbearing potential/contraception in males and females
Women of childbearing potential have to use effective contraception during treatment. Decreased
serum estradiol and progesterone concentrations have been reported in women treated with human
leukocyte interferon.
IntronA must be used with caution in fertile men.
Combination therapy with ribavirin
33
Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be
taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in
combination with ribavirin. Females of childbearing potential and their partners must each use an
effective contraceptive during treatment and for 4 months after treatment has been concluded. Male
patients and their female partners must each use an effective contraceptive during treatment and for 7
months after treatment has been concluded (see ribavirin SPC).
Pregnancy
There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA
is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Combination therapy with ribavirin
Ribavirin therapy is contraindicated in women who are pregnant.
Breast-feeding
It is not known whether the components of this medicinal product are excreted in human milk.
Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior
to initiation of treatment.
Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment
with IntronA, and therefore it is recommended that they avoid driving or operating machinery.
See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in
combination with ribavirin in patients with chronic hepatitis C.
In clinical trials conducted in a broad range of indications and at a wide range of doses (from
6 MIU/m
2
/week in hairy cell leukaemia up to 100 MIU/m
2
/week in melanoma), the most commonly
reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were
often reversible within 72 hours of interruption or cessation of treatment.
Adults
In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in
combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three
times a week. In
Table 1
the frequency of patients reporting (treatment related) undesirable effects is
presented from clinical trials in naïve patients treated for one year. Severity was generally mild to
moderate. The adverse reactions listed in
Table 1
are based on experience from clinical trials and post-
marketing. Within the organ system classes, adverse reactions are listed under headings of frequency
using the following categories: very common (≥1/10); common (≥1/100 to <1/10);
uncommon
(≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known. Within each
frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1.
Adverse reactions reported during clinical trials or following the marketing use of IntronA alone
or in combination with ribavirin
System Organ Class
Adverse Reactions
Infections and infestations
Very common:
Common:
Uncommon:
Rarely:
Pharyngitis*, infection viral*
Bronchitis, sinusitis, herpes simplex (resistance), rhinitis
Bacterial infection
Pneumonia
§
, sepsis
Blood and lymphatic system disorders
Very common:
Leukopaenia
34
Common:
Very rarely:
Not known
:
Thrombocytopaenia, lymphadenopathy, lymphopenia
Aplastic anaemia
Pure red cell aplasia, idiopathic thrombocytopenic purpura,
thrombotic thrombocytopenic purpura
Immune system disorders
§
Very rarely:
Not known:
Sarcoidosis, exacerbation of sarcoidosis
Systemic lupus erythematosus, vasculitis, rheumatoid
arthritis (new or aggravated), Vogt-Koyanagi-Harada
syndrome, acute hypersensitivity reactions including
urticaria, angioedema, bronchoconstriction, anaphylaxis
§
Endocrine disorders
Common:
Very rarely:
Hypothyroidism
§
, hyperthyroidism
§
Diabetes, aggravated diabetes
Metabolism and nutrition disorders
Very common:
Common:
Very rarely:
Anorexia
Hypocalcaemia, dehydration, hyperuricemia, thirst
Hyperglycaemia, hypertriglyceridaemia
§
, increased appetite
Psychiatric disorders
§
Very common:
Depression, insomnia, anxiety, emotional lability*,
agitation, nervousness
Confusion, sleep disorder, libido decreased
Suicide ideation
Suicide, suicide attempts, aggressive behaviour (sometimes
directed against others), psychosis including hallucinations
Homicidal ideation, mental status change
§
, mania, bipolar
disorders
Common:
Rarely:
Very rarely:
Not known:
Nervous system disorders
§
Very common:
Common:
Dizziness, headache, concentration impaired, mouth dry
Tremor, paresthesia, hypoesthesia, migraine, flushing,
somnolence, taste perversion
Peripheral neuropathy
Cerebrovascular haemorrhage, cerbrovascular ischaemia,
seizure, impaired consciousness, encephalopathy
Mononeuropathies, coma
§
Uncommon:
Very rarely:
Not known:
Eye disorders
Very common:
Common:
Vision blurred
Conjunctivitis, vision abnormal, lacrimal gland disorder, eye
pain
Retinal haemorrhages
§
, retinopathies (including macular
oedema), retinal artery or vein obstruction
§
, optic neuritis,
papilloedema, loss of visual acuity or visual field, cotton-
wool spots
§
Rarely:
Ear and labyrinth
Common:
Very rarely:
Vertigo, tinnitus
Hearing loss, hearing disorder
Cardiac disorders
Common:
Rarely:
Very rarely:
Not known:
Palpitation, tachycardia
Cardiomyopathy
Myocardial infarction, cardiac ischaemia
Congestive heart failure, pericardial effusion, arrhythmia
Vascular disorders
Common:
Very rarely:
Hypertension
Peripheral ischaemia, hypotension
§
Respiratory, thoracic and mediastinal
disorders
Very common:
Dyspnoea*, coughing*
35
Common:
Epistaxis, respiratory disorder, nasal congestion, rhinorrhea,
cough nonproductive
Pulmonary infiltrates
§
, pneumonitis
§
Very rarely:
Gastrointestinal disorders
Very common:
Nausea/vomiting, abdominal pain, diarrhoea, stomatitis,
dyspepsia
Stomatitis ulcerative, right upper quadrant pain, glossitis,
gingivitis, constipation, loose stools
Pancreatitis, ischaemic colitis, ulcerative colitis, gingival
bleeding
Periodontal disorder NOS, dental disorder NOS
§
Common:
Very rarely:
Not known:
Hepatobiliary disorders
Common:
Very rarely:
Hepatomegaly
Hepatotoxicity, (including fatality)
Skin and subcutaneous tissue disorders
Very common:
Common:
Alopecia, pruritus*, skin dry*, rash*, sweating increased
Psoriasis (new or aggravated)
§
, rash maculopapular, rash
erythematous, eczema, erythema, skin disorder
Stevens Johnson syndrome, toxic epidermal necrolysis,
erythema multiforme
Very rarely:
Musculoskeletal and connective tissue
disorders
Very common:
Common:
Very rarely:
Myalgia, arthralgia, musculoskeletal pain
Arthritis
Rhabdomyolysis, myositis, leg cramps, back pain
Renal and urinary disorders
Common:
Very rarely:
Micturition frequency
Renal failure, renal insufficiency, nephrotic syndrome
Reproductive system and breast
disorders
Common:
Amenorrhea, breast pain, dysmenorrhea, menorrhagia,
menstrual disorder, vaginal disorder
General disorders and administration
site conditions
Very common:
Injection site inflammation, injection site reaction*, fatigue,
rigors, pyrexia
§
, flu-like symptoms
§
, asthenia, irritability,
chest pain, malaise
Injection site pain
Injection site necrosis, face oedema
Common:
Very rarely:
Weight decrease
*These events were only common with IntronA alone
§
See section 4.4
These undesirable effects have also been reported with IntronA alone.
The undesirable effects seen with hepatitis C are representative of those reported when IntronA
is
administered in other indications, with some anticipated dose-related increases in incidence. For
example, in a trial of high-dose adjuvant IntronA
treatment in patients with melanoma, incidences of
fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-
like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C
trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of
patients, respectively), in comparison with the mild to moderate severity usually associated with lower
36
Investigations
Very common:
Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with
pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy,
that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients
without prior evidence of cardiac disease (see section 4.4).
A wide variety of autoimmune and immune-mediated disorders have been reported with alpha
interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or
aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including
mononeuropathies (see also section
4.4).
Clinically significant laboratory abnormalities, most frequently occurring at doses greater than
10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in
haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and
serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase
in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis
subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.
Children and adolescent population
Chronic Hepatitis C - Combination therapy with ribavirin
In clinical trials of 118 children and adolescents (3 to 16 years of age), 6 % discontinued therapy due
to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent
population studied was similar to that observed in adults, although there is a paediatric- specific
concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of
9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during
treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of
44
th
percentile, which was below the median of the normative population and less than their mean
baseline height (48
th
percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height
percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from
the start of treatment to the end of long-term follow-up (up to 5 years). During combination therapy
for up to 48 weeks with IntronA and ribavirin, growth inhibition is observed, the reversibility of which
is uncertain. In particular, decrease in mean height percentile from baseline to the end of the long-term
follow-up was most prominent in prepubertal age children (see section 4.4).
Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients
(2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult
patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression,
emotional lability, and somnolence) (see
section 4.4). In addition, injection site disorders, pyrexia,
anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents
compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for
anaemia and neutropaenia.
The adverse reactions listed in
Table 2
are based on experience from the two multicentre children and
adolescent clinical trials. Within the organ system classes, adverse reactions are listed under headings
of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 2
Adverse reactions very commonly and commonly reported during clinical trials inchildren
and adolescent patients treated with IntronA in combination with ribavirin
System Organ Class
Adverse Reactions
Infection and infestations
Very common:
Common:
Viral infection, pharyngitis
Fungal infection, bacterial infection, pulmonary infection, otitis
media, tooth abscess, herpes simplex, urinary tract infection,
vaginitis, gastroenteritis
Neoplasms benign, malignant
37
and unspecified (including
cysts and polyps)
Common:
Neoplasm (unspecified)
Blood and lymphatic system
disorders
Very common:
Common:
Anaemia, neutropaenia
Thrombocytopaenia, lymphadenopathy
Endocrine disorders
Very common:
Common:
Hypothyroidism
§
,
Hyperthyroidism
§
, virilism
Metabolism and nutrition
disorders
Very common:
Common:
Anorexia
Hypertriglyceridemia
§
, hyperuricemia, increased appetite
Psychiatric disorders
§
Very common:
Common:
Depression, emotional lability, insomnia
Suicidal ideation, aggressive reaction, confusion, behaviour
disorder, agitation, somnambulism, anxiety, nervousness, sleep
disorder, abnormal dreaming, apathy
Nervous system disorders
§
Very common:
Common:
Headache, dizziness
Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia,
hyperaesthesia, concentration impaired, somnolence
Eye disorders
Common:
Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Vascular disorders
Common:
Flushing, pallor
Respiratory, thoracic and
mediastinal disorders
Common:
Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal
irritation, rhinorrhea, sneezing
Gastrointestinal disorders
Very common:
Common:
Diarrhoea, vomiting, nausea, abdominal pain
Mouth ulceration, stomatitis ulcerative, stomatitis, right upper
quadrant pain, dyspepsia, glossitis, gastroesophogeal reflux, rectal
disorder, gastrointestinal disorder, constipation, loose stools,
toothache, tooth disorder
Hepatobiliary disorders
Common:
Hepatic function abnormal
Skin and subcutaneous tissue
disorders
Very common:
Common:
Alopecia, rash
Photosensitivity reaction, maculopapular rash, eczema, acne, skin
disorder, nail disorder, skin discolouration, pruritus, dry skin,
erythema, bruise, sweating increased
Musculoskeletal and
connective tissue disorders
Very common:
Arthralgia, myalgia, musculoskeletal pain
Renal and urinary disorders
Common:
Enuresis, micturition disorder, urinary incontinence
Reproductive system and
breast disorders
Common:
Female
: amenorrhea, menorrhagia, menstrual disorder, vaginal
disorder
Male:
testicular pain
General disorders and
38
administration site
conditions
Very common:
Injection site inflammation, injection site reaction, fatigue, rigors,
pyrexia
§
, influenza-like symptoms
§
, malaise, irritability
Chest pain, asthenia, oedema, injection site pain
Common:
Investigations
Very common:
Growth rate decrease (height and/or weight decrease for age)
§
Injury and poisoning
Common:
§
See section 4.4
Skin laceration
No case of overdose has been reported that has led to acute clinical manifestations. However, as for
any pharmacologically active compound, symptomatic treatment with frequent monitoring of vital
signs and close observation of the patient is indicated.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: interferon alfa-2b, ATC code: L03A B05
IntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant
DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of
approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically
engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.
The activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b
protein corresponding to 2.6 x l0
8
IU. International Units are determined by comparison of the activity
of the recombinant interferon alfa-2b with the activity of the international reference preparation of
human leukocyte interferon established by the World Health Organisation.
The interferons are a family of small protein molecules with molecular weights of approximately
15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or
various synthetic and biological inducers. Three major classes of interferons have been identified:
alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain
several different molecular species of interferon. More than 14 genetically distinct human alpha
interferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.
Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface.
Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly
asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species
specificity. Studies with other interferons have demonstrated species specificity. However, certain
monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure
to human type 1 interferons.
The results of several studies suggest that, once bound to the cell membrane, interferon initiates a
complex sequence of intracellular events that include the induction of certain enzymes. It is thought
that this process, at least in part, is responsible for the various cellular responses to interferon,
including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and
such immunomodulating activities as enhancement of the phagocytic activity of macrophages and
augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities
may contribute to interferon's therapeutic effects.
39
Recombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing both
animal and human cell culture systems as well as human tumour xenografts in animals. It has
demonstrated significant immunomodulatory activity
in vitro
.
Recombinant interferon alfa-2b also inhibits viral replication
in vitro
and
in vivo
. Although the exact
antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell
metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are
unable to leave the cell.
Chronic hepatitis B
Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates
that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been
observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity
and mortality has been observed.
Interferon alfa-2b (6 MIU/m
2
3 times a week for 6 months) has been given to children with chronic
active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover
children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of
depression were observed.
Chronic hepatitis C in adult patients
In adult patients receiving interferon in combination with ribavirin, the achieved sustained response
rate is 47 %. Superior efficacy has been demonstrated with the combination of pegylated interferon
with ribavirin (sustained response rate of 61 % achieved in a study performed in naïve patients with a
ribavirin dose > 10.6 mg/kg, p < 0.01).
IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical
trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of
IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologic
response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C
confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/ml), a liver
biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic
hepatitis, and abnormal serum ALT.
IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with
ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were
followed for an additional 6 months after the end of treatment for the determination of sustained
virologic response. Sustained virologic response rates for treatment groups treated for one year with
IntronA alone or in combination with ribavirin (from two studies) are shown in
Table 3
.
Co-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold for
the treatment of chronic heptatitis C in naïve patients. HCV genotype and baseline virus load are
prognostic factors which are known to affect response rates. The increased response rate to the
combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The
relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most
difficult to treat subgroup of patients (genotype 1 and high virus load) (
Table 3
).
Response rates in these trials were increased with compliance. Regardless of genotype, patients who
received IntronA in combination with ribavirin and received ≥ 80 % of their treatment had a higher
sustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment
(56 % vs. 32 % in trial C/I98-580).
Table 3
Sustained virologic response rates with IntronA + ribavirin (one year of
treatment) by genotype and viral load
40
HCV Genotype
I
N=503
C95-132/I95-143
I/R
N=505
C95-132/I95-143
I/R
N=505
C/I98-580
All Genotypes
16 %
41 %
47 %
Genotype 1
9 %
29 %
33 %
Genotype 1
≤ 2 million
copies/ml
25 %
33 %
45 %
Genotype 1
> 2 million
copies/ml
3 %
27 %
29 %
Genotype 2/3
31 %
65 %
79 %
I
IntronA (3 MIU 3 times a week)
I/R
IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)
HCV/HIV Co-infected patients
Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies,
patients who received IntronA plus ribavirin, were less likely to respond than patients who received
pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is
presented in
Table 4.
Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which
enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with
HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plus
ribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a
follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled
95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV.
Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 µg /week based on
weight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (3 MIU TIW) plus ribavirin
(800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period
of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml
(Amplicor) who were treated for 24 weeks with a 6-month follow-up period.
Table 4
Sustained virological response based on genotype after IntronA in combination with
ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in
HCV/HIV co-infected patients
Study 1
1
Study 2
2
pegylated
interferon
alfa-2b
(1.5 µg/kg/
week) +
ribavirin
(800 mg)
IntronA
(3 MIU TIW) +
ribavirin
(800 mg)
p
value
a
pegylated
interferon
alfa-2b (100
or
150
c
µg/week)
+ ribavirin
(800-
1,200 mg)
d
IntronA
(3 MIU TIW)
+ ribavirin
(800-
1,200 mg)
d
p
value
b
All
27 % (56/205) 20 % (41/205) 0.047 44 % (23/52)
21 % (9/43)
0.017
Genotype 1,
4
17 % (21/125)
6 % (8/129)
0.006 38 % (12/32)
7 % (2/27)
0.007
Genotype 2,
3
44 % (35/80)
43 % (33/76)
0.88 53 % (10/19)
47 % (7/15)
0.730
MIU = million international units; TIW = three times a week.
41
a: p value based on Cochran-Mantel Haenszel Chi square test.
b: p value based on chi-square test.
c: subjects < 75 kg received 100 µg/week pegylated interferon alfa-2b and subjects ≥ 75 kg received 150 µg/week
pegylated interferon alfa-2b.
d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.
1
Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.
2
Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.
Relapse patients
A total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronA
monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA
increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic
hepatitis C (48.6 % vs. 4.7 %). This enhancement in efficacy included loss of serum HCV
(< 100 copies/ml by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was
sustained when measured 6 months after the end of treatment.
Long-Term efficacy data
In a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-
2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic
response and assess the impact of continued viral negativity on clinical outcomes. 462 patients
completed at least 5 years of long-term follow-up and only 12 sustained responders' out of
492 relapsed during this study.
The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with
a 95 % Confidence Interval of
[95 %, 99 %].
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (with or without ribavirin)
results in long-term clearance of the virus providing resolution of the hepatic infection and clinical
'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients
with cirrhosis (including hepatocarcinoma).
Chronic hepatitis C in children and adolescent population
Three clinical trials have been conducted in children and adolescents; two with standard interferon and
ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin
were less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.
Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable
HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in
two multicentre trials and received IntronA 3 MIU/m
2
3 times a week plus ribavirin 15 mg/kg per day
for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 %
male, 80 % Caucasian, and 78 % genotype 1,64 % ≤ 12 years of age. The population enrolled mainly
consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained
virological response rates in children and adolescents were similar to those in adults. Due to the lack
of data in these two multicentre trials for children with severe progression of the disease, and the
potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b
needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).
Study results are summarized in
Table 5
.
Table 5.
Sustained virological response in previously untreated children and
adolescents
IntronA 3 MIU/m
2
3 times a week
+
ribavirin 15 mg/kg/day
Overall Response
a
(n=118)
54 (46 %)*
42
Genotype 1 (n=92)
33 (36 %)*
Genotype 2/3/4 (n=26)
21 (81 %)*
*Number (%) of patients
a. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during
follow-up period
Long-term efficacy data
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C
patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all
enrolled subjects completed this study of which 75 % (42/56) were sustained
responders. The purpose
of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess
the impact of continued viral negativity on clinical outcomes for patients who were sustained
responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but
one of the paediatric subjects remained sustained virologic responders during long-term follow-up
after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for
continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients
treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at
follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with
cirrhosis (including hepatocarcinoma).
Results from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin
In a multicentre trial children and adolescents 3 to 17 years of age with compensated chronic
hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 μg/m
2
plus ribavirin
15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load.
All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received
treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and
63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate
hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential
for undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirin
needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs
section 4.4). The study results are summarized in
Table 6.
Table 6.
Sustained virological response rates (n
a,b
(%)) in previously untreated children
and adolescents by genotype and treatment duration – All subjects
n = 107
24 weeks
48 weeks
All Genotypes
26/27 (96 %)
44/80 (55 %)
Genotype 1
-
38/72 (53 %)
Genotype 2
14/15 (93 %)
-
12/12 (100 %) 2/3 (67 %)
Genotype 4 - 4/5 (80 %)
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of
detection=125 IU/ml.
b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.
c: Patients with genotype 3 low viral load (< 600,000 IU/ml) were to receive 24 weeks of treatment while
those with genotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment.
5.2 Pharmacokinetic properties
The pharmacokinetics of IntronA were studied in healthy volunteers following single 5 million IU/m
2
and 10 million IU doses administered subcutaneously, at 5 million IU/m
2
administered intramuscularly
43
Genotype 3
c
and as a 30-minute intravenous infusion. The mean serum interferon concentrations following
subcutaneous and intramuscular injections were comparable. C
max
occurred three to 12 hours after the
lower dose and six to eight hours after the higher dose. The elimination half-lives of interferon
injections were approximately two to three hours, and six to seven hours, respectively. Serum levels
were below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous and
intramuscular administration resulted in bioavailabilities greater than 100 %.
After intravenous administration, serum interferon levels peaked (135 to 273 IU/ml) by the end of the
infusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscular
administration of medicinal product, becoming undetectable four hours after the infusion. The
elimination half-life was approximately two hours.
Urine levels of interferon were below the detection limit following each of the three routes of
administration.
Interferon neutralising factor assays were performed on serum samples of patients who received
IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies
which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors
developing in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %.
The detectable titres are low in almost all cases and have not been regularly associated with loss of
response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was
observed apparently due to the low titres.
Children and adolescent population
Multiple-dose pharmacokinetic properties for IntronA injection and ribavirin capsules in children and
adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in
Table 7
. The
pharmacokinetics of IntronA and ribavirin (dose-normalized) are similar in adults and children or
adolescents.
44
Table 7.
Mean (% CV) multiple-dose pharmacokinetic parameters for IntronA and ribavirin
capsules when administered to children or adolescents with chronic hepatitis C
Parameter
Ribavirin
15 mg/kg/day as 2 divided
doses
(n = 17)
IntronA
3 MIU/m
2
3 times a week
(n = 54)
T
max
(hr)
1.9 (83)
5.9 (36)
C
max
(ng/ml)
3,275 (25)
51 (48)
AUC*
29,774 (26)
622 (48)
Apparent clearance l/hr/kg
0.27 (27)
Not done
*AUC
12
(ng.hr/ml) for ribavirin; AUC
0-24
(IU.hr/ml) for IntronA
5.3 Preclinical safety data
Although interferon is generally recognised as being species specific, toxicity studies in animals were
conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no
evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with
20 x 10
6
IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in
monkeys given 100 x 10
6
IU/kg/day for 3 months.
In studies of interferon use in non-human primates, abnormalities of the menstrual cycle have been
observed (see section 4.4).
Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic
in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in
offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in
Macaca
mulatta
(rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose
of 2 million IU/m
2
. Abortion was observed in all dose groups (7.5 million, 15 million and
30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups
(corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of
2 million IU/m
2
). High doses of other forms of interferons alpha and beta are known to produce dose-
related anovulatory and abortifacient effects in rhesus monkeys.
Mutagenicity studies with interferon alfa-2b revealed no adverse events.
45
IntronA plus ribavirin
No studies have been conducted in juvenile animals to examine the effects of treatment with interferon
alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results
have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with
ribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination with
ribavirin).
6.
6.1 List of excipients
Disodium phosphate anhydrous
Sodium dihydrogen phosphate monohydrate
Edetate disodium
Sodium chloride
M-cresol
Polysorbate 80
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
18 months.
Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25ºC for a period
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the product is not used during the seven-day period, it cannot be put back in the
refrigerator for a new storage period and must be discarded.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
For storage conditions of the medicinal product, see section 6.3.
6.5 Nature and contents of container
0.5 ml of solution (corresponding to 5 MIU) in a single dose vial (type I glass) with a stopper
(halobutyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene).
Pack sizes of 1.
Or
0.5 ml of solution (corresponding to 5 MIU) in a single dose vial (type I glass) with a stopper
(halobutyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene)
The pack size also contains 1 injection syringe, 1 injection needle and 1 cleansing swab.
Packs sizes of 1, 6 or 12.
Not all pack sizes may be marketed.
46
6.6 Special precautions for disposal
Not all dose forms and strengths are appropriate for some indications. Please make sure to select an
appropriate dose form and strength.
IntronA solution for injection or infusion may be injected directly after withdrawal of the appropriate
doses from the vial with a sterile injection syringe.
Detailed instructions for the subcutaneous use of the product are provided with the package leaflet
(refer to “How to self inject IntronA”).
Preparation of IntronA for intravenous infusion: The infusion is to be prepared immediately prior to
use. Any size vial may be used to measure the required dose; however, final concentration of
interferon in sodium chloride solution must be not less than 0.3 million IU/ml. The appropriate dose of
IntronA is withdrawn from the vial(s), added to 50 ml of 9 mg/ml (0.9 %) sodium chloride solution for
injection in a PVC bag or glass bottle for intravenous use and administered over 20 minutes.
No other medicinal product can be infused concomitantly with IntronA.
As with all parenteral medicinal products, prior to administration inspect IntronA, solution for
injection or infusion, visually for particulate matter and discolouration. The solution should be clear
and colourless.
Any unused product must be discarded after withdrawal of the dose.
7.
SP Europe
73, rue de Stalle
B-1180 Bruxelles
Belgium
8.
EU/1/99/127/015
EU/1/99/127/016
EU/1/99/127/017
EU/1/99/127/018
9.
Date of first authorisation : 9 March 2000
Date of latest renewal :
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/
47
1.
Marketing Authorisation Holder:
Manufacturer:
73, rue de Stalle
Industriepark 30
B-1180 Bruxelles
B-2220 Heist-op-den-Berg
Belgium
Belgium
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Rue de Stalle/Stallestraat 73
B-1180 Bruxelles/Brussel/Brüssel
Tél/Tel: + 32-(0)2 370 92 11
Luxembourg/Luxemburg
Rue de Stalle 73
B-1180 Bruxelles/Brüssel
Belgique/Belgien
Tél/Tel: + 32-(0)2 370 92 11
България
Magyarország
305
SP Europe
SP Labo N.V.
Ийст Парк Трейд Център
Бул. „Н.Й.Вапцаров” 53А, ет. 2
BG-София 1407
Тел.: +359 2 806 3030
Alkotás u. 53.
H-1123 Budapest
Tel.: +36 1 457-8500
Česká republika
Ke Štvanici 3
CZ-186 00 Praha 8
Tel: +420 221771250
Malta
168 Christopher Street
MT-VLT02 Valletta
Tel: + 356-21 23 21 75
Danmark
Lautrupbjerg 2
DK-2750 Ballerup
Tlf: + 45-44 39 50 00
Nederland
Walmolen 1
NL-3994 DL Houten
Tel: + 31-(0)800 9999000
Deutschland
Thomas-Dehler-Straße 27
D-81737 München
Tel: + 49-(0)89 627 31-0
Norge
Pb. 398
N-1326 Lysaker
Tlf: + 47 67 16 64 50
Eesti
Järvevana tee 9
EE-11314 Tallinn
Tel: + 372 654 96 86
Österreich
Am Euro Platz 2
A-1120 Wien
Tel: +43-(0) 1 813 12 31
Ελλάδα
Αγίου Δημητρίου 63
GR-174 55 Άλιμος
Tηλ: + 30-210 98 97 300
Polska
Ul. Taśmowa 7
PL-02-677 Warszawa
Tel.: + 48-(0)22 478 41 50
España
Josefa Valcárcel, 38
E-28027 Madrid
Tel: + 34-91 321 06 00
Portugal
Rua Agualva dos Açores 16
P-2735-557 Agualva-Cacém
Tel: +351-21 433 93 00
France
34 avenue Léonard de Vinci
F-92400 Courbevoie
Tél: + 33-(0)1 80 46 40 40
România
Şos. Bucureşti-Ploieşti, nr. 17-21,
Băneasa Center, et. 8, sector 1
RO-013682 Bucureşti
Tel. + 40 21 233 35 30
Ireland
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW
Tel: +44-(0)1 707 363 636
Slovenija
Dunajska 22
SI-1000 Ljubljana
Tel: + 386 01 3001070
Ísland
Hörgatún 2
IS-210 Garðabær
Sími: + 354 535 70 00
Slovenská republika
Strakova 5
SK-811 01 Bratislava
Tel: + 421 (2) 5920 2712
Italia
Via fratelli Cervi snc,
Centro Direzionale Milano Due
Palazzo Borromini
I-20090 Segrate (Milano)
Tel: + 39-02 21018.1
Suomi/Finland
PL 46/PB 46
FIN-02151 Espoo/Esbo
Puh/Tel: + 358 (0)9 804 650
306
Κύπρος
Οδός Αγίου Νικολάου, 8
CY-1055 Λευκωσία
Τηλ: +357-22 757188
Sverige
Box 7152
S-192 07 Sollentuna
Tel: + 46-(0)8 522 21 500
Latvija
Bauskas 58a -401
Rīga, LV-1004
Tel: + 371-7 21 38 25
United Kingdom
Shire Park
Welwyn Garden City
Hertfordshire AL7 1TW - UK
Tel: + 44-(0)1 707 363 636
Lietuva
Kęstučio g. 65/40
LT-08124 Vilnius
Tel. + 370 52 101868
This leaflet was last approved on
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
307
HOW TO SELF INJECT INTRONA
The following instructions explain how to inject IntronA yourself. Please read the instructions
carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-
inject IntronA. Do not attempt to inject yourself unless you are sure you understand the procedure and
requirement of self-injection.
Preparation
Collect necessary items before you begin:
-
the IntronA multidose pen;
-
a needle for subcutaneous injection (provided in the packaging);
-
a cleansing swab (provided in the packaging).
Wash your hands carefully. Use the injection needles provided in the packaging only for IntronA. Use a
new injection needle for each dose. Be sure the solution is at room temperature (up to 25°C) at the time of
injection.
Diagrams A and B show you all the different parts of the pen and the injection needle. The most
important parts to note are as follows:
-
The push button scale tells you what dose has been set.
-
The colour coding strip pink and the push button are at the bottom of the pen as it is held cap
up.
-
The pen can only be fully capped when the triangle on the cap scale is aligned with the dosage
indicator on the barrel.
Cap
Cap
scale
Needle
Rubber
membrane
Reservoir
Dosage
indicator
Pen barrel
Colour
coding
Push
button
scale
Push
button
Diagram A
Diagram B
308
Measuring the dose of IntronA
Take the pen out of the refrigerator about one-half hour before administering the dose so that the
solution in the pen is at room temperature when it is injected.
When you are ready to give your injection prepare your pen as follows:
Check that IntronA solution for injection is clear and colourless in appearance prior to use. If it does
not have a clear uniform appearance or if it contains any particles, do not use.
Pull off the cap of the pen and disinfect the rubber membrane (see Diagram C) with one cleansing
swab.
Diagram C
Remove the protective tab from the injection needle. Note that the rear portion of the injection needle
is revealed once the protective tab is removed (see Diagram D).
Diagram D
Gently push the injection needle onto the pen as shown in Diagram E. (Notice that the rear portion of
the injection needle will pierce through the rubber membrane that you disinfected previously). Now
screw the injection needle onto the pen securely by turning it in a clockwise direction (see Diagram F).
Diagram E
Diagram F
First, pull off the outer injection needle cap (Diagram G). Then, pull off the inner injection needle cap
carefully, bearing in mind that the injection needle will now be exposed (Diagram H). Keep the outer
injection needle cap for later use.
309
Diagram G
Diagram H
The pen is now ready to use. Since a small amount of air may collect in the injection needle and
reservoir during storage, the next step is to remove any air bubbles. This is called performing the Air-
Shot.
Hold the pen with the injection needle point upwards.
Tap the reservoir with your finger so that any air bubbles rise to the top of the reservoir, just below the
injection needle (Diagram I).
Diagram I
Hold the pen by the barrel and turn the reservoir in the direction as indicated by the arrow in Diagram
J (clockwise) until you feel it click.
Diagram J
Keeping the pen pointing upwards, press the push button up fully and see if a drop of solution appears
at the injection needle tip (Notice the drop at the tip of injection needle in Diagram K below).
310
Diagram K
If no drop appears, use a different pen, and return the faulty pen to your provider.
Note: some air may remain in the pen, but this is not important as you have removed the air from the
injection needle and the dose will be accurate.
Replace the pen cap with the ‘triangle’ opposite the dosage indicator as seen in Diagram L.
Diagram L
The pen is now ready to set the dose. For the next step hold the pen in the middle of the barrel. This
will allow the push button to move freely, ensuring that the correct dose is set.
To set the required dose, hold the pen horizontally by the barrel with one hand. With the other hand,
turn the cap in a clockwise direction indicated by the arrow in Diagram M. You will observe the push
button rising, indicating the dose set. To set the correct dose, turn the cap as many times as indicated
as follows:
311
Number of “turns” and
“clicks”
Corresponding doses (million IU) using
IntronA, solution for injection, multidose pen
60 million IU/pen:
1 full turn (5 clicks)
5
6 clicks
6
7 clicks
7
8 clicks
8
9 clicks
9
2 full turns (10 clicks)
10
11 clicks
11
Diagram M
12 clicks
12
13 clicks
13
14 clicks
14
3 full turns (15 clicks)
15
16 clicks
16
17 clicks
17
18 clicks
18
19 clicks
19
4 full turns (20 clicks)*
20
*4 full turns correspond to the maximum dose to be administered in one injection. The pen is designed to deliver its contents
of 60 million IU in doses ranging from 5 to 20 million IU. The pen will deliver a maximum of 12 doses of 5 million IU
over
a period not to exceed 4 weeks.
The push button scale will show you the dose set (see Diagram N below). For doses corresponding to
full turns, the scale should line up with the correct dose marking. For doses corresponding to clicks
intermediate between full turns, the scale should line up between the two appropriate full-turn dose
markings. At that point check that you have the correct dose.
312
Diagram N
After each complete turn make sure that the triangle is opposite the dosage indicator (see Diagram O).
If you have set a wrong dose, simply turn the cap back (anti-clockwise) as far as you can until the push
button is fully home and start again. Once the correct dose is set you are ready to give the injection.
Diagram O
Injecting the solution
Select the injection site. The best sites for injection are tissues with a layer of fat between skin and
muscle: thigh, outer surface of the upper arm (you may need the assistance of another person to use
this site), abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or
outer surface of the arm for injection. Change your injection site each time.
Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry.
With one hand, pinch a fold of loose skin. With your other hand, pick up the pen and hold it as you
would a pencil. Insert the needle into the pinched skin at an angle of approximately 45°.
Then press the push button down fully (see Diagram P).
Diagram P
Keeping the push button down, leave the injection needle in place for a few seconds to allow the
solution to distribute under the skin, then remove.
Carefully replace the outer injection needle cap (see Diagram Q).
313
Diagram Q
Completely unscrew the injection needle assembly using an anti-clockwise turning motion as shown in
Diagram R. Then carefully lift it off the pen and discard the capped injection needle (see Diagram S).
Diagram R
Diagram S
Replace the pen cap with the triangle once again opposite the dosage indicator as shown in Diagram T.
Then return the pen to the refrigerator.
Diagram T
314
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