Download Imunovir®500mg Tablets

Imunovir®500mg Tablets
Inosine Acedoben Dimepranol
Imunovir® 500mg Tablets
Inosine Acedoben Dimepranol
ANTIVIRAL IMMUNOTHERAPY
Imunovir | 1
Imunovir® 500mg Tablets
Inosine Acedoben Dimepranol
Imunovir® tablets contain as an active pharmaceutical ingredient, 500mg
Inosine Acedoben Dimepranol (also known as Inosine Pranobex [BAN]), an
immunomodulating agent with specific antiviral properties. Imunovir® is an
acceptable oral solid dose therapy with a well established safety profile that
is indicated for the treatment of:
•
•
Mucocutaneous infections due to herpes simplex virus
(type I and/or type II)
Genital warts as adjunctive therapy to podophyllin or carbon dioxide laser
•
Subacute sclerosing panencephalitis (SSPE)
Imunovir® is a Prescription Only Medicine and is available in blister packs
of 100 tablets.
PIP code 100 Tablets:
001-3987
Trade Price:
£39.50
Imunovir® is marketed worldwide and is known by various trade names in different countries
e.g. Delimmun® and Isoprinosine®. The active ingredient is also known in different territories
under different names such as Inosine Pranobex (BAN), Inosiplex and Methisoprinol.
Immunomodulation
Inosine Acedoben Dimepranol (IAD) is an immunomodulatory agent that
mediates anti-viral properties. IAD supports the immune system through
modulation of T-cell proliferation, T-cell function, natural killer cell activity
and phagocytosis.
Studies have shown that IAD induced an enhanced lymphocyte
transformation response to inactivated HSV antigen in patients with genital
herpes (Corey et al 1979). Lomnitzer (1988) demonstrated the in-vitro ability
of IAD to enhance the proliferation of peripheral blood mononuclear cells.
IAD has also been shown to elicit a PBMC response coupled with an increase
in Interferon activity in patients suffering from SSPE (Gadoth et al 1989).
Miglietta et al (1980) showed that IAD brought about an increase in
monocyte and neutrophil phagocytosis.
2 | Imunovir
Tsang et al (1985) observed, through in-vitro analysis in healthy elderly
humans, that the presence of IAD was associated with the restoration of
ConA-induced lymphocyte proliferation, natural killer cell activity, neutrophil
chemotaxis and IL-2 production to normal or near normal levels in 90%,
85.3%, 84.6% and 71.4% respectively of the subjects studied.
Petrova et al (2010) demonstrated that IAD, administered at a dose of 3g IAD
per day for five days repeated weekly for three weeks, was capable of
increasing cytokine levels (IFN-γ, IL-10 and TNF-α) in healthy patients at Day 7
and Day 10.
The pivotal role played by the cell-mediated immune system in controlling
duration and severity of, and recovery from, viral infection provides the basis
for treatment with immunopharmacological agents such as IAD (Miller 1984).
Genital Herpes
IAD is one of the treatment options for the treatment of primary genital herpes.
In an 812 patient study Talbot and Menday (1985) found that the clinical
response was highly significant in favour of IAD (4g/day for seven days) in
patients with both primary lesions irrespective of stage or recurrent episodes
when compared to placebo.
In addition the mean reduction in total “symptom score” (based on the pretreatment and post-treatment evaluation of pain, itching and inflammation
on a 4-point scale) was significantly greater in primary cases in the active
group (p<0.01). The greatest symptomatic relief attributable to IAD was relief
of itching and reduction of inflammation. This was particularly apparent for
all patients with herpes labialis treated in the prodromal stages.
In a double blind placebo controlled clinical study, IAD was shown to
produce a significant reduction in recurrence rate (Figure 1), virus shedding
and overall severity of the disease (Miller 1984). Therapy began with an initial
dosage of IAD at 3g/day initiated within 24 hours of a recurrence outbreak for
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the first 5 days of each recurrence with the dosage reduced to 1g/day on day
6 until the next recurrence occurred at which time the cycle was repeated for
6 months. In the follow-up open phase for another 6 months, all patients
received Isoprinosine® at the same treatment schedule as for the first 6
months. Isoprinosine® produced a significant reduction in recurrence rate,
virus shedding and overall severity of the disease.
A large number of concomitant medications were used with no indications of
any drug interaction with Isoprinosine®.
Miller (1984) concluded that IAD has significant therapeutic and
epidemiological importance in the management and control of HSV
infections.
Patients with recurrences (%)
Recurrences in Males
50
40
30
20
IAD
10
Placebo
0
0-1
2-3
Recurrences / 6 months
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4-9
Patients with recurrences (%)
Recurrences in Females
50
40
30
20
IAD
10
Placebo
0
2-3
0-1
4-9
Recurrences / 6 months
Figure 1: The effect of IAD on the frequency of recurrences in genital herpes
(Adapted from Miller 1984)
Byrne et al (1988) in a double blind placebo controlled clinical study further
compared episodic therapy (4g IAD per day for 5 days from the first sign of
recurrence) to continuous therapy (4g IAD per day for 5 days from the first
sign of recurrence followed by a maintenance dose of 1g IAD per day for 1
year) – the final six months was an open label study. Mean recurrence rates
remained significantly less than the pre-treatment mean during the follow-up
period of 80 to 450 days after cessation of therapy. The results of the study
presented in Figure 2 showed that continuous treatment exhibited a
statistically significant reduction in the frequency of recurrence of genital
herpes infection with the effect persisting for one year.
Number of recurrences per month
Episodic treatment
Continuous treatment
IAD
Placebo
IAD
Placebo
Pre-treatment
0.92
0.77
1.13
0.96
Treatment
0.99
0.81
0.60
0.86
Changes
0.07
0.04
-0.53*
-0.11
* p < 0.01 compared with pre-treatment baseline
Figure 2: The effect of IAD on the number of recurrences of genital herpes per month
(Adapted from Byrne et al 1988)
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In a 12 week double-blind placebo-controlled trial in 39 patients with a high
frequency of herpes simplex labialis recurrences (median number of
recurrences in the year before the trial was 9.25±2), IAD was shown to affect a
greater reduction of recurrences than the placebo group (p<0.02). The
dosing regime was 70mg/kg IAD for 7 days which was repeated every four
weeks for three cycles (Galli et al 1984).
Genital Warts
IAD through its immunomodulating capability represents a unique oral systemic
therapy for the treatment of genital HPV infection.
In a 38 patient randomized placebo-controlled study, Georgala et al (2006)
investigated the efficacy and safety of IAD (50mg/kg daily for 12 weeks) as a
treatment of cervical condylomata acuminata that was resistant to at least one
conventional therapy. Results showed a statistically significant differential
between the treatment and placebo groups (p < 0.01) which remained
significant when an intention to treat analysis was performed (p < 0.01). Patients
that exhibited complete recovery did not experience any recurrence within the
12 month follow-up period.
Davidson-Parker et al (1988) conducted a UK multi-centred, randomised,
placebo controlled study in 51 patients suffering from genital warts for at least
one year. Results showed that a four week course of IAD (3g per day) improved
the clinical response to conventional treatment (primary podophyllin or
trichloroacetic acid). Of the 27 patients that attended all of the follow-up visits
(2, 4, 8 and 12 weeks post study entry), the conventional therapy supplemented
by IAD had a significant effect in eradicating the warts and reducing the extent
of lesions compared to conventional treatment alone (Figure 3).
Conventional therapy
with IAD (14 patients)
Conventional therapy
(13 patients)
Complete eradication of warts
5*
3
Reduction of number of warts
10
7
Reduction in extent of lesions
11**
5
General response
11
8
* p < 0.05 ** p = 0.05
Figure 3: Assessment of the effects on IAD in combination with conventional therapies
(Adapted from Davidson-Parker et al 1988)
6 | Imunovir
Sadoul and Beuret (1984) studied the clinical effects of combined IAD/CO2 laser
therapy compared to CO2 laser therapy alone in 126 patients suffering from
cervical condylomata and vulvo-vaginal condylomata that were refractory to
multiple treatments (diathermic coagulation, cryotherapy and podophyllin).
Results showed that combined IAD/CO2 laser therapy reduced the clinical failure
rate to 6.25% after one treatment compared to 45.16% in the group that
received only CO2 laser therapy. The number of failures was reduced to zero
following three treatments with combined IAD/CO2 laser therapy (Figure 4).
1st treatment
CO2 laser therapy
(62 patients – 38 CC, 24 VC)
IAD CO2 laser therapy
(64 patients – 29 CC, 35 VC)
2nd treatment
3rd treatment
CC
VC
CC
VC
CC
VC
12
16
2
10
2
8
Total: 28
Total: 12
Total: 10
CC
VC
CC
VC
CC
VC
2
2
1
1
0
0
Total: 4
Total: 2
Total: 0
CC: cervical condylomata VC: vulvo-vaginal condylomata
Figure 4: Assessment of the effect of IAD in combination with CO2 laser therapy –
comparison of failures (Adapted from Sadoul and Beuret 1984)
In an open label 60 patient trial Jurisin et al (1986) observed higher rates of
healing of genital warts in male patients that received IAD in combination
with podophyllin when compared to those patient that received podophyllin
alone.
Similarly Kovacs et al (1989) concluded that IAD (3g per day for 4 weeks) in
combination with podophyllin compared with podophyllin only resulted in
shortened healing times in female patients suffering from condylomatous
lesions.
Hicks and Kelly (1997) combined the diverse clinical study data from fourteen
clinical trials that evaluated IAD as a drug therapy in the management of
genital HPV infections. The meta-analysis of the clinical data from the trials
focused on the use of IAD as an adjunct to conventional therapy.
The clinical data shows that the use of IAD in the treatment of genital warts
provides a 24-26% additional success rate over the effects of conventional
Imunovir | 7
therapy alone with regard to total lesion clearance and improvement in
cellular morphology in surrounding tissue harbouring active HPV-infected
cells (Figure 5).
Additionally the meta-analysis of all of the clinical study data revealed that IAD
produced a 22-29% greater effect over conventional or control therapy where
•
the lesions are single or multiple in site or quantity
•
the lesions are situated externally (limited to the perineum and not
including perianal warts in either sex) or internally (including vulvovaginal
or endocervical sites in females but not urethral meatal warts in males)
Difference in proportion
of successes from
baseline when using
adjuvant Imunivor®
(% of patients with
cleared lesions
Adjuvant use of Imunivor® improves
treatment success (measured by the
clearance of external genital warts).
50
40
30
25
33%
31%
25%
13%
10
0
Baseline control
(conventional
treatment for
genital warts)
-2%
-10
-20
-30
-40
Study 1
Study 2
Study 3
Study 4
(Davidson Parker)
(Jurisin)
(Kovacs)
(Sadoul and Beuret)
Pooled Data
(meta-analysis)
In Figure 5, the comparison is with
conventional treatment for external
genital warts while the bars show
the difference achieved by using
adjuvant Imunivor® in four trials;
95% confidence intervals are
shown (vertical lines)
Pooling the data by meta-analysis
(extreme right) gives a clearer and
(as the confidence intervals show) a
more consistent summary of the
individual studies.
Figure 5: The effect of using Imunovir® as an adjunct to conventional therapy
(Adapted from Hicks and Kelly 1997)
8 | Imunovir
Subacute Sclerosing Panencephalitis (SSPE)
IAD has been used in many clinical conditions in which sub-acute or chronic
viral infections have been associated with a reduced host immune response.
This is classically found in SSPE, in which a reduced immune function,
characterised by reduced interferon production, is related to persisting
activity of mutated measles virus.
In a 121 patient study the efficacy and safety of oral IAD alone versus
combined treatment with oral IAD and intraventricular alpha interferon in
patients diagnosed with SSPE was evaluated in a Phase III trial (1997-2002).
There were no statistically significant differences between treatment groups
on any measure of efficacy. Although there was no significant difference
between the treatment groups in rates of clinically defined satisfactory
outcomes the observed rates were higher than spontaneous remission rates
reported in the literature suggesting that treatment was superior to no
treatment. The rate of adverse events was statistically lower in the IAD
treatment group when compared to the combination treatment group
(Gascon 2003).
In a retrospective study using historical controls involving 59 clinical centres
in Japan, Fukuyama et al (1987) concluded that the use of IAD in the
treatment of SSPE was useful, with relatively high safety, in that it improved
the survival curve of patients with SSPE and caused a delay in the progress of
clinical symptoms. The data is entirely consistent with the expected effect of
interferon therapy and that the benefits of Isoprinosine® appear
independently of interferon therapy and are additive to it.
Fukuyama et al (1987) make the important point that clinical benefits do not
appear in every case however IAD was particularly efficacious in the
treatment of the slowly progressive form of the disease which accounts for
70% of all SSPE cases.
Ginsberg (1989) in a clinical study comprising 98 prospectively selected
patients in USA and Canada showed that the probability of long-term survival
Imunovir | 9
beyond six years was 62% in treated patients compared to 6-26% in the control
groups albeit some doubt was raised with respect to the control groups as they
were not prospectively randomised.
Horiguchi and Ohya (1995) reported prolonged effectiveness of both
neurological symptoms and life expectancy after oral inosiplex and intrathecal
interferon therapy. Anlar (1998) studied a combination of subcutaneous
interferon-beta and Isoprinosine® according to an open design with stabilization
or improvement observed in 3 of the 7 patients. Gokcil (1999) followed up 8
patients treated with intraventricular interferon-alpha in combination with
Isoprinosine® or Isoprinosine® alone and noted that all patients receiving
combined treatment had survived after 3-4 years of follow up with 3 patients
improving or stabilizing.
In an 18 patient study by Gascon et al (1993) that used IAD in combination with
α-interferon by intraventricular injection, an improvement in the disability index
was found in 3 patients, with the index remaining stable in 5 constituting a
response of 44% over a follow-up period of 12 to 40 months. Gascon et al (1993)
recommended this combined therapy as treatment of choice in the few cases of
SSPE presenting after widespread vaccination policies.
Garg (2002) stated that a combination of oral IAD and intraventricular
interferon alfa appears to be the best effective treatment for SSPE albeit
patients responding to treatment need to receive it life long. The only
effective solution to this disease remains immunisation against measles.
10 | Imunovir
Safety
IAD has been used for almost 40 years receiving its first approval in 1971
in Argentina and its first European approval in Italy in 1979.
Since 1971 approximately 1.45 billion tablets have been prescribed
worldwide.
Since 1971 there have been approximately 1500 adverse reactions
reported in postmarket surveillance.
Imunovir | 11
References
Immunomodulation
Corey L., Chiang W., Reeves W., Stamm W., Brewer L. and Holmes K. (1979) Effect of Isoprinosine on
the cellular immune response in initial genital herpes virus infection. Clinical Research, 27 (1), 41A.
Gadoth N., Kott E., Levin S. and Hahn T. (1989) The interferon system in subacute sclerosing
panencephalitis and its response to Isoprinosine. Brain and Development, 11 (5), 308-312.
Lomnitzer R. (1988) Isoprinosine potentiation of human peripheral blood mononuclear response
to mitogens: kinetics and effect on expression of the IL-2 receptor and the activity of interleukin2. Journal of Clinical Laboratory Immunology, 27, 91-96.
Miglietta A., Ventura M., Ressa A. and Dammacco F. (1980) The in-vitro effect of methisoprinol on
phagocytes, monocytes and neutrophilic granulocytes. 5th Congress of the Italian Society of
Immunology and Immunopathology.
Miller R. D. (1984) Safety and efficacy of inosine pranobex in recurrent genital herpes simplex
infections. Presented at a Clinical Meeting of the Praed Street Clinic, St. Mary's Hospital;
September, London, UK, 8-11.
Petrova M., Jelev D., Ivanova A. and Krastev Z. (2010) Isoprinosine Affects Serum Cytokine Levels in
Healthy Adults. Journal of Interferon and Cytokine Research, 30 (4), 5-9.
Tsang K. Y., Pan J. F., Swanger D. L. and Fudenberg H. H. (1985) In-vitro restoration of immune
responses in aging humans by Isoprinosine. International Journal of Immunopharmacology,
7(2), 199-206.
Genital Herpes
Byrne M. A., Lawrence A. G., Walker G. D., O’Neill B. B., Csonka G. W., John J., Shanson D. C., Jeffries
D. J. and Harris J. R. W. (1988) Suppression of recurrent genital herpes by inosine pranobex: effects
of episodic and continuous treatment. Current Therapeutic Research [USA], 43(4), 681-688.
Galli M., Lazzarin A., Moroni M. and Zanussi C. (1984) Treatment of recurrent viral infectious
diseases by methisoprinol. In: Fudenberg H. H., Whitten H. D., Ambrogi F., eds.
Immunomodulation: New Frontiers and Advances. New York, NY, USA, Plenum Press, 385-397.
Miller R. D. (1984) Safety and efficacy of inosine pranobex in recurrent genital herpes simplex
infections. Presented at a Clinical Meeting of the Praed Street Clinic, St. Mary's Hospital;
September, London, UK, 8-11.
Talbot D. J. and Menday A. P. (1985) Inosine pranobex in mucocutaneous herpes. The Lancet [UK],
325, 877.
12 | Imunovir
Genital Warts
Davidson-Parker J., Dinsmore W., Khan M. H., Hicks D. A., Morris C. A. and Morris D. F. (1988)
Immunotherapy of genital warts with inosine pranobex and conventional treatment:
doubleblind, placebo-controlled study. Genitourinary Medicine, 64, 383-386.
Georgala S., Katoulis A. C., Befon A., Georgala C. and Rigopoulos D. (2006) Oral inosiplex in the
treatment of cervical condylomata acuminata: a randomised placebo-controlled trial. BJOG, 113,
1088–1091.
Hicks, DA. and Kelly A. (1997) Meta—analysis of clinical studies for use of Imunovir in treatment of
genital warts. 6th Congress of EADV, Dublin, JEADV, 9 (suppl 1),S149, [FC146] September 11-15.
Jurisin D., Isailovic G., Veljkovic M. and Djekic L. (1986) Topical use of cytostatics and
immunostimulants in the treatment of genital warts. Presented at Dermatotherapeutic Days,
Arandjelovac, Yugoslavia, September.
Kovacs L., Molnar G. B. and Farkas E. (1989) Experience with Isoprinosine in the treatment of
condyloma acuminatum (in Hungarian). Presented at Roundtable Symposium on Immunology,
Hungarian Immunology Congress, Szeged, Hungary, Oct 25-28.
Sadoul G. and Beuret T. (1984) Treatment of cervical and vulvar condylomata with CO2 laser
combined with immunostimulant (in French). Revue Française de Gynécologie et d’Obstétrique,
79 (11), 681-684.
SSPE
Anlar B., Yalaz K., Kose G. and Saygi S. (1998) Beta interferon plus inosiplex in the treatment of
Subacute sclerosing panencephalitis. Journal of Child Neurology, 13 (11), 557-59.
Fukuyama Y., Nihei K., Matsumoto S., Ebina T., Kamoshita S., Sato T., Arima M., Yabuuchi H., Ueda
S., Ohtahara S., Takeshita K., Kurokawa T., Ishida N., Okuno Y., Tateishi J. and Sakuma A. (1987)
Clinical effects of MND-19 (Inosiplex) on subacute sclerosing panencephalitis. Brain and
Development, 9, 270-282.
Garg R. K. (2002) Subacute sclerosing panencephalitis. Postgrad Medical Journal, 78, 63–70.
Gascon G. (2003) Randomized treatment of inosiplex versus combined inosiplex and
intraventricular interferon-alpha in subacute sclerosing panencephalitis (SSPE): international
multicentre study. Journal of Child Neurology, 18, 819-827.
Gascon G., Yamani S., Crowell J., Stigsby B., Nester B., Nester M., Kanaan I. and Jallu A. (1993)
Combined oral Isoprinosine-intraventricular α-interferon therapy for subacute sclerosing
panencephalitis. Brain and Development, 15(5), 346-354.
Ginsberg T. (1989) Isoprinosine in subacute sclerosing panencephalitis: Confirmation and
extension of beneficial clinical results in the US and Canada by a recent study in Japan. Third
International Symposium on SSPE, India.
Imunovir | 13
Gokcil Z., Odabasi Z., Demirkaya S., Eroglu E. and Vural O. (1999) Alpha-interferon and
Isoprinosine in adult onset subacute sclerosing panencephalitis. Journal of Neurological
Sciences, 162(1), 62-64.
Horiguchi Y. and Ohya T. (1995) Successful treatment of subacute sclerosing panencephalitis
with long-term intrathecal large dose of alpha-interferon – a case report. No To Hattatsu,
27 (3), 231- 37.
14 | Imunovir
Imunovir® 500mg Tablets
Inosine Acedoben Dimepranol
Each tablet contains 500mg Inosine Acedoben Dimepranol (INN, also known as inosine pranobex*) which is the
p-acetamidobenzoic acid salt of N,N-dimethylamino-2-propanol [DIP.PAcBA] and β-inosine in a 3:1molar ratio. *British Approved
Name (BAN) the non-proprietary designation.
PRESCRIBING INFORMATION: Pharmaceutical Form: White to off-white tablets with a faint amine odour, engraved with a
score-line on one side and 'DN' on the other. The score-line is only to facilitate breaking for ease of swallowing and not to
divide into equal doses. Therapeutic indications: Imunovir® tablets are indicated in the management of:
a) Mucocutaneous infections due to herpes simplex virus (type l and/or type II)
b) Genital warts as adjunctive therapy to podophyllin or carbon dioxide laser
c) Subacute sclerosing panencephalitis (SSPE)
Posology and method of administration: ORAL ADMINISTRATION. Adults: Mucocutaneous herpes simplex: 1g q.d.s. (4g daily),
for 7-14 days. Genital warts: 1g t.d.s. (3g daily), for 14-28 days as adjunctive therapy to podophyllin or carbon dioxide laser.
Subacute sclerosing panencephalitis (SSPE): 50-100mg/kg daily, in divided doses every 4 hours. Children: No information is
available in children. Elderly: No dosage alterations are necessary in the elderly. Contraindications: There are no known
contraindications to therapy with this drug.
Special Warnings and special precautions for use: As the inosine component of Imunovir® is metabolised to uric acid, it
should be used with caution in patients with renal impairment, a history of gout or hyperuricaemia.
Interaction with other medicaments and other forms of interaction: None known.
Use in pregnancy and lactation: Although animal tests have shown no teratogenic effect, the use of Imunovir® in women
where pregnancy is suspected or confirmed should be avoided.
Undesirable effects: The only consistently observed drug-related side effect is a transient elevation (usually remaining within
normal range) of urine and serum uric acid levels, which usually return to baseline values a few days after the end of treatment.
Side effects recorded in >1% of clinical studies of 3 months or longer and reported infrequently in postmarketing
surveillance: Gastrointestinal: Nausea with or without vomiting, epigastric discomfort, Hepatic: Elevation of transaminases,
alkaline phosphatase or blood urea nitrogen (BUN) level, Dermatological: Itching, skin rashes, Nervous system: Headaches,
vertigo, fatigue or malaise, Other: Arthralgia.
Side effects recorded in <1% of clinical studies of 3 months or longer and reported rarely in postmarketing surveillance:
Gastrointestinal: Diarrhoea, constipation, Nervous system: Nervousness, drowsiness or insomnia, Genitourinary: Polyuria
(increased urine volume). Overdose: There has been no experience of overdosage with Imunovir®. However serious adverse
effects apart from increased levels of uric acid in the body, seem unlikely in view of the animal toxicity studies. Treatment
should be restricted to symptomatic and supportive measures.
Legal Category: POM (Prescription only Medicine). Product License Number: PL 39972/0001
Marketing Authorisation Holder:
KoRa Corporation Ltd. t/a KoRa Healthcare,
Swords Business Park, Swords, Co. Dublin, Ireland.
Trade Price: £39.50
PIP Code 100 Tablets: 001-3987
EAN Code 5702191001280
Date of issue: 11th March 2013
The cover shows a herpes simplex virus
Imunovir | 15
Imunovir® 500mg Tablets
Inosine Acedoben Dimepranol
ANTIVIRAL IMMUNOTHERAPY
16 | Imunovir
Imunovir | 17
UK_Prof_Imunovir_VE4.0_Mar13
KoRa Healthcare
Swords Business Park, Swords, Co. Dublin, Ireland.
UK Tel: 0845-303 8631 UK Fax: 0845-303 8632
www.kora-health.com
KoRa
HEALTHCARE