IMVAMUNE Suspension for injection Ref.[50013] Active ingredients: Smallpox, live attenuated

General

• As with any other vaccine, vaccination with IMVAMUNE may not result in protection in all cases.
• As with all vaccines, appropriate medical treatment and supervision should always be available to treat rare cases of anaphylactic reactions following the administration of the vaccine.
• IMVAMUNE should not be administered intravascularly.

Monitoring and Laboratory Tests

Replicating smallpox vaccines have been associated with myopericarditis. If a vaccinated subject exhibits signs and symptoms potentially associated with a cardiac disorder (e.g. chest pain or discomfort, dyspnea, or palpitations), ECG and troponin I tests should be performed. In case of ECG changes or troponin I elevations, further cardiologic examination should be performed.

7.1 Special Populations

Pregnant Women

Available human data on IMVAMUNE administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy. Animal reproductive studies did not reveal any evidence of impaired fertility or harm to the fetus. IMVAMUNE should be administered to pregnant women only if they are at risk of infection with variola virus or other orthopoxviruses, and if the benefit of immunization outweighs the potential risks to the mother and fetus.

Breast-feeding

Safety during lactation has not been established. It is unknown if vaccine antigens or antibodies are excreted in human milk. IMVAMUNE should be administered to women who are breastfeeding only if they are at risk of infection with variola virus or other orthopoxviruses, and if the benefit of immunization outweighs the potential risks.

Pediatrics

Pediatrics (<18 years of age): IMVAMUNE has not been studied in subjects below 18 years of age. Before the eradication of smallpox disease, smallpox vaccination was administered routinely during childhood since the benefits were considered to outweigh the risks. IMVAMUNE should be administered to children only if they are at risk of infection with variola virus or other orthopoxviruses, and if the benefit of immunization outweighs the potential risks to the child.

Geriatrics

Geriatrics (≥56 years of age): IMVAMUNE has been administered to 120 subjects 56 to 80 years of age. No overall differences in safety and immunogenicity were observed between these subjects and those <56 years of age.

Immunosuppressed Individuals

The use of IMVAMUNE in immunosuppressed patients is supported by clinical trials which include individuals who are human immunodeficiency virus (HIV) infected (CD4 ≥100 cells/µL), and individuals with atopic dermatitis (AD). (See Section 14.1 for more details). An adequate immune response may be diminished in HIV positive individuals as well as in other patients with immunodeficiency or patients receiving immunosuppressive therapy.

8.1 Adverse Reaction Overview

Safety was assessed in 20 completed clinical trials where approximately 13,700 doses were given to 7414 subjects. The most common local adverse drug reactions at the injection site after vaccine administration are pain, erythema, induration and swelling. The most common systemic adverse drug reactions observed after vaccination are fatigue, headache, myalgia, and nausea. Most of the reported adverse drug reactions were of mild to moderate intensity and resolved within the first seven days following vaccination. No trends have been identified suggesting the occurrence of any particular unexpected adverse reactions or classes of adverse reactions following the administration of IMVAMUNE.

Cardiac AESIs were reported to occur in 1.4% (91/6,640) of IMVAMUNE recipients and 0.2% (3/1,206) of placebo recipients who were smallpox vaccine-naïve. Cardiac AESIs were reported to occur in 2.1% (16/762) of IMVAMUNE recipients who were smallpox vaccine-experienced. The higher proportion of IMVAMUNE recipients who experienced cardiac AESIs was driven by 28 cases of asymptomatic post-vaccination elevation of troponin-I in two studies, that used a different troponin assay than was used in the other previous studies, and had no placebo controls. The clinical significance of these asymptomatic post-vaccination elevations of troponinI is unknown. Among the cardiac AESIs reported, 6 cases (0.08%) were considered to be causally related to IMVAMUNE vaccination and included tachycardia, electrocardiogram T wave inversion, abnormal electrocardiogram, electrocardiogram ST segment elevation, abnormal electrocardiogram T wave, and palpitations. None of the cardiac AESIs considered causally related to study vaccination were considered serious. Furthermore, despite close cardiac monitoring, no confirmed case of myocarditis, pericarditis, endocarditis or any other type of cardiac inflammatory disease (or related syndromes) was recorded.

In addition, IMVAMUNE has been tested in individuals with contraindications to receiving replicating smallpox vaccines, i.e. HIV infected persons and AD patients. The safety profile of IMVAMUNE in immune compromised subjects has been shown to be comparable to that recorded for healthy individuals. IMVAMUNE has been studied in more than 690 subjects infected with HIV to evaluate its immunogenicity and safety in an immunocompromised population. Since HIV directly infects T helper cells, and also indirectly impairs other immune system responses, HIV infection can be considered as being exemplary also for other forms of immunodeficiency.

AD subjects developed slightly more frequent and more intense reactions than are typically observed after vaccination (local skin reactions such as injection site erythema, injection site swelling and injection site pruritus; general symptoms like headache, myalgia, chills, nausea, and fatigue). No indication or trend could be detected that a vaccination with IMVAMUNE worsens the intensity of AD.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Data sources: Summarized 6-month safety data of all completed clinical Phase I trials POXMVA-001, POX-MVA-002, POX-MVA-007, POX-MVA-030; Phase I/II trials POX-MVA-010, POX-MVA-009 and HIV-POL-002 (IMVAMUNE control group only); Phase II trials POX-MVA004, POX-MVA-005, POX-MVA-008, POX-MVA-011, POX-MVA-023, POX-MVA-024, POXMVA-028, POX-MVA-029, POX-MVA-037 and HIV-NEF-004 (IMVAMUNE control group only); and Phase III trials POX-MVA-013 and POX-MVA-006 (total N=6755)

Doses ranging from 1 × 10⁶to 1 × 10⁸ Inf.U were administered in studies POX-MVA-001, POXMVA-002 and POX-MVA-004; in all remaining studies, the standard dose was generally utilized.

The following populations were included:

• Vaccinia-naïve, healthy, 18-55 years of age
• Vaccinia-experienced, healthy, 18-55 years of age
• IMVAMUNE -experienced, healthy, 20-57 years of age
• Vaccinia-experienced, healthy, elderly 56-80 years of age
• Vaccinia-naïve, HIV-1 infected, 18-55 years of age
• Vaccinia-experienced, HIV-1 infected, 18-55 years of age
• Vaccinia-naïve, atopic dermatitis (AD), 18-40 years of age
• Vaccinia-naïve, allergic rhinitis (AR), 18-40 years of age

The following frequencies of Adverse Drug Reactions (n= 6755) have been reported in these completed clinical trials with IMVAMUNE (Table 2).

Table 2. Adverse Drug Reactions Reported in Completed IMVAMUNE Clinical Trials (N=6755):

Individuals with atopic dermatitis (AD)

In a non-placebo controlled clinical trial that compared the safety of IMVAMUNE in individuals with AD to healthy individuals, individuals with AD reported erythema (61.2%) and swelling (52.2%) at the injection site with a higher frequency than healthy individuals (49.3% and 40.8%, respectively). The following general symptoms were reported more frequently in individuals with AD compared to healthy individuals: headache (33.1% vs. 24.8%), myalgia (31.8% vs. 22.3%), chills (10.7% vs. 3.8%), nausea (11.9% vs. 6.8%), and fatigue (21.4% vs. 14.4%). 7% of the individuals with AD in clinical trials with IMVAMUNE experienced a flare-up or worsening of their skin condition during the course of the trial.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

There were no safety concerns with regard to haematological parameters, clinical chemistry or urine analysis across studies.

9.2 Drug Interactions Overview

Concomitant administration of combination antiretroviral therapy in the majority of the HIV-1 infected study population did not reveal any undesirable interaction regarding the efficacy and safety of IMVAMUNE.

Use with other vaccines

Interactions with other vaccines have not been established. Therefore, concomitant administration of other vaccines should be avoided. If co-administration with another vaccine is indicated, immunization should be carried out on separate limbs. To minimize the potential risk of interactions, it is recommended to administer killed vaccines >2 weeks and live vaccines ≥4 weeks before or after administration of IMVAMUNE.

Use with immunoglobulins

Interaction with concomitant administration of immunoglobulins has not been established. Interactions with other drugs have not been established.