Adverse reactions : תופעות לוואי

4.8   Undesirable effects

a. Summary of the safety profile
In 5 clinical trials, ProQuad was administered without concomitant vaccines to 6038 children 12 through 23 months of age. The children in these studies received either the current refrigerator-stable formulation or an earlier formulation of ProQuad. Children in these studies were monitored for six weeks post vaccination. The safety profiles were comparable for the two different formulations after a single dose.
The only vaccine-related systemic adverse reactions reported at a significantly greater rate in individuals who received the earlier formulation of ProQuad compared to individuals who received the measles, mumps, and rubella vaccine manufactured by MSD and Varicella Vaccine live (Oka/Merck) were fever (≥39.4°C rectal equivalent or abnormal) and measles-like rash. Both fever and measles-like rash usually occurred within 5 to 12 days following the vaccination, were of short duration and resolved with no long- term sequelae. Pain/tenderness/soreness at the injection site was reported at a statistically lower rate in individuals who received ProQuad.

The only vaccine related injection site adverse reaction that was more frequent among recipients of ProQuad than among recipients of Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by MSD was rash at the injection site.

Following ProQuad given alone in 7 clinical trials, the observed rates of fever (≥39.4°C rectal equivalent) ranged from 10.1% to 39.4%. In comparison, following ProQuad given concomitantly with Prevenar and/or hepatitis A vaccine in 3 clinical trials, the observed rates of reported fever (≥39.4°C rectal equivalent) ranged from 15.2% to 27.2%.

In a clinical trial of ProQuad administered concomitantly with Infanrix Hexa, the rates of fever (≥38.0°C rectal equivalent) were 69.3% following concomitant administration, 61.1% following ProQuad alone, and 57.3% following Infanrix Hexa alone; the rates of fever (≥39.4°C rectal equivalent) were 22.6% following concomitant administration, 20.5% following ProQuad alone, and 15.9% following Infanrix Hexa alone.

The overall safety profile of ProQuad was comparable whether it was administered concomitantly or alone.

Children who received a second dose of ProQuad
In eight clinical studies, the overall rates of adverse reactions after a second dose of ProQuad were generally similar to, or lower than, those seen with the first dose. In three of these studies, the rates of injection site erythema and swelling were statistically significantly higher after the second dose than after the first dose; however, in the remaining five studies, the rates of each of these reactions were similar after the first and second dose. The fever rate in all eight studies was lower after the second dose than after the first dose.

Children who received ProQuad intramuscularly
The general safety profiles of the IM and SC administration routes were comparable; however, fewer subjects experienced injection site adverse reactions in the IM group after each dose (see section 5.1 for study description).

Children who received ProQuad at 4 through 6 years of age after primary immunization with Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by MSD The rates and types of adverse reactions seen in the study group that received ProQuad were generally similar to those seen in the groups that received Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by MSD (see section 5.1 for study description).

No specific studies have been conducted in individuals from 2 years of age who had not previously received measles, mumps, rubella, and varicella vaccines.

The most common adverse events reported with the use of ProQuad were: injection site reactions including pain/tenderness/soreness, redness, swelling or bruising; fever (≥39.4°C rectal equivalent); irritability; rash (including measles-like rash, varicella-like rash, and injection site rash); upper respiratory infection; vomiting and diarrhoea.
 b. Tabulated list of adverse reactions

The following adverse reactions were reported as vaccine related by the investigator in individuals after a single dose of ProQuad. Several adverse events were solicited in the clinical studies and are designated with the symbol (‡). Additionally, other adverse events have been reported with post-marketing use of ProQuad and/or in clinical studies and post-marketing use of either the measles, mumps, and rubella vaccine manufactured by MSD, the monovalent component vaccines of the measles, mumps, and rubella vaccine manufactured by MSD, or Varicella Vaccine live (Oka/Merck). The frequency of these adverse events is qualified as "not known" when it cannot be estimated based on the available data.

Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000); Not known (cannot be estimated from the available data)


Adverse reactions                                           Frequency Infections and infestations
Ear infection, Gastroenteritis, Otitis media,
Uncommon
Pharyngitis, Viral infection, Viral rash
Cellulitis, Respiratory tract infection, Skin infection,
Rare
Tonsillitis, Varicella+ ‡, Viral conjunctivitis
Aseptic meningitis*, Encephalitis*, Epididymitis,
Not known
Herpes zoster*, Infection, Measles, Orchitis, Parotitis
Blood and lymphatic system disorders
Leukocytosis, Lymphadenopathy                               Rare
Lymphadenitis, Thrombocytopenia                             Not known Immune system disorders
Hypersensitivity                                            Rare
Anaphylactoid reaction, Anaphylactic reaction,
Not known
Angioedema, Face oedema, and Peripheral oedema
Metabolism and nutrition disorders
Decreased appetite                                          Uncommon
Dehydration                                                 Rare
Psychiatric disorders
Irritability                                                Common
Crying, Sleep disorder                                      Uncommon
Apathy, Clinging, Restlessness                              Rare
Nervous system disorders
Febrile seizure*, Somnolence                                Uncommon
Ataxia, Seizure, Headache, Hyperkinesia,
Rare
Hypersomnia, Lethargy, Tremor
Bell’s palsy, Cerebrovascular accident, Dizziness,
Encephalopathy*, Guillain-Barré syndrome, Measles           Not known inclusion body encephalitis (see section 4.3), Ocular
palsies, Paraesthesia, Polyneuropathy, Subacute sclerosing panencephalitis*, Syncope, Transverse myelitis
Eye disorders
Conjunctivitis, Eye discharge, Blepharitis, Eye irritation, Eye swelling, Ocular hyperaemia, Increased Rare lacrimation, Ocular discomfort
Eyelid oedema, Optic neuritis, Retinitis, Retrobulbar
Not known neuritis
Ear and labyrinth disorders
Ear pain                                                Rare
Neurosensory deafness                                   Not known
Vascular disorders
Flushing, Pallor                                        Rare
Extravasation                                           Not known
Respiratory, thoracic, and mediastinal disorders
Cough, Respiratory tract congestion, Rhinorrhoea        Uncommon
Sinus disorder, Sneezing, Wheezing                      Rare
Bronchospasm, Bronchitis, Pneumonitis (see section 4.3), Pneumonia, Rhinitis, Sinusitis,           Not known
Oropharyngeal pain
Gastrointestinal disorders
Diarrhoea, Vomiting                                     Common
Abdominal pain upper, Nausea, Stomatitis                Rare
Abdominal pain, Haematochezia                           Not known
Skin and subcutaneous tissue disorders
Measles-like rash‡, Rash, Varicella-like rash‡          Common
Dermatitis (including contact and atopic),
Uncommon
Rubella-like rash‡, Urticaria, Erythema
Cold sweat, Exfoliative dermatitis, Drug eruption,
Henoch-Schönlein purpura, Papular rash, Pruritus,       Rare
Skin discolouration, Skin lesion, Zosteriform rash
Erythema multiforme, Panniculitis, Purpura, Skin
Not known induration, Stevens-Johnson syndrome
Musculoskeletal and connective tissue disorders
Arm pain, Musculoskeletal stiffness                     Rare
Arthritis, Arthralgia*, Musculoskeletal pain, Myalgia,
Not known
Swelling
General disorders and administration site conditions
Fever‡, Erythema‡ or Pain/Tenderness/Soreness‡ at
Very common the injection site
Ecchymosis or Swelling‡ at the injection site,
Common
Injection site rash‡
Asthenia, Fatigue, Injection site haemorrhage,
Uncommon
Injection site induration, Injection site mass, Malaise
Influenza like illness, Injection site exfoliation,
Injection site discolouration, Injection site pruritus,
Rare
Injection site reaction, Injection site scar,
Hyperthermia, Pain

Injection site complaints (Pain, Oedema, Urticaria,
Haematoma, Induration, Mass, Vesicles),                 Not known
Inflammation, Papillitis
Investigations
Weight loss                                             Rare
Injury, poisoning and procedural complications
Contusion                                               Rare
Social circumstances
Activities of daily living impaired                     Rare
+
Varicella caused by vaccine strain was observed in post-marketing use with Varicella Vaccine live (Oka/Merck).
‡ Adverse events solicited in clinical trials.
* See section c
 c. Description of selected adverse reactions

Aseptic meningitis
Cases of aseptic meningitis have been reported following measles, mumps, and rubella vaccination.
Although a causal relationship between other strains of mumps vaccine and aseptic meningitis has been shown, there is no evidence to link Jeryl Lynn mumps vaccine to aseptic meningitis.

Complications associated with varicella
Complications of varicella from vaccine strain including herpes zoster and disseminated disease such as aseptic meningitis and encephalitis have been reported in immunocompromised and immunocompetent individuals.

Febrile seizures
Febrile seizures have been reported in children receiving ProQuad. Consistent with clinical study data on the timing of fever and measles-like rash, a post-marketing observational study in children 12 to 60 months of age revealed an approximate two-fold increase (0.70 per 1000 vs. 0.32 per 1000 children) in the risk of febrile seizures in the 5- to 12-day timeframe after a first dose of ProQuad (N=31,298) compared with concomitant administration of the measles, mumps, and rubella vaccine manufactured by MSD, and the Varicella Vaccine live (Oka/Merck) (N=31,298). These data suggest one additional case of febrile seizure per 2600 children vaccinated with ProQuad compared with separate administration of the measles, mumps, and rubella vaccine manufactured by MSD, and the Varicella Vaccine live (Oka/Merck). These data were confirmed by a post-marketing observational study sponsored by the U.S.
Centers for Disease Control and Prevention. In the 30-day timeframe following vaccination, no increased risk of febrile seizures was observed (see section 5.1).

Encephalitis and encephalopathy
In severely immunocompromised individuals inadvertently vaccinated with measles-containing vaccine, measles inclusion body encephalitis, pneumonitis, and fatal outcome as a direct consequence of disseminated measles vaccine virus infection have been reported (see section 4.3); disseminated mumps and rubella vaccine virus infection has also been reported.

SSPE
There is no evidence that measles vaccine can cause SSPE. There have been reports of SSPE in children who did not have a history of infection with wild-type measles but did receive measles vaccine. Some of these cases may have resulted from unrecognized measles in the first year of life or possibly from the measles vaccination. The results of a retrospective case-controlled study conducted by the US Centers for 
Disease Control and Prevention show that the overall effect of measles vaccine has been to protect against SSPE by preventing measles with its inherent risk of SSPE.

Arthralgia and/or arthritis
Arthralgia and/or arthritis (usually transient and rarely chronic), and polyneuritis are features of infection with wild-type rubella and vary in frequency and severity with age and gender, being greatest in adult females and least in prepubertal children. Following vaccination in children, reactions in joints are generally uncommon (0 to 3%) and of brief duration. In women, incidence rates for arthritis and arthralgia are generally higher than those seen in children (12 to 20%), and the reactions tend to be more marked and of longer duration. Symptoms may persist for a matter of months or on rare occasions for years. In adolescent girls, the reactions appear to be intermediate in incidence between those seen in children and adult women. Even in older women (35 to 45 years), these reactions are generally well tolerated and rarely interfere with normal activities.

Chronic arthritis
Chronic arthritis has been associated with wild-type rubella infection and has been related to persistent virus and/or viral antigen isolated from body tissues. Only rarely have vaccine recipients developed chronic joint symptoms.

Cases of herpes zoster in clinical studies
In a clinical trial, 2 cases of herpes zoster were reported in 2108 healthy subjects 12 through 23 months of age who were vaccinated with one dose of ProQuad and followed for 1 year. Both cases were unremarkable and no sequelae were reported.

Active surveillance data in children vaccinated with Varicella Vaccine live (Oka/Merck) and followed for 14 years after vaccination showed no increase in the frequency of herpes zoster compared to children with prior wild-type varicella during the pre-vaccine era. These surveillance data actually suggest that varicella-vaccinated children may have a lower risk of herpes zoster. However, the long term effect of varicella vaccination on the incidence of herpes zoster is unknown at present. There are no long-term data currently available with ProQuad (see section 5.1).

Transmission
Based on post-marketing surveillance, the possibility exists that varicella vaccine virus (Oka/Merck strain) may rarely be transmitted to contacts of recipients of ProQuad who develop or do not develop a varicella-like rash (see section 4.4).
 d. Other special populations

Immunocompromised individuals (see section 4.3)
Necrotising retinitis has been reported post-marketing in immunocompromised individuals.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il