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Local injection site reaction was the most commonly reported adverse reaction after COVID-19 vaccine administration during clinical trials. In general, the rates and severity of the reactions were slightly higher after the second dose compared to after the first.[66080] [66120] After Pfizer-BioNTech COVID-19 vaccine administration, pain (84.1%), erythema or redness (9.5%), and swelling (10.5%) at the injection site were the most common reactions in patients 16 years and older. Most local reactions resolved within 3 days, but some patients reported symptoms for up to 36 days. About one-third (28.3% to 32%) of patients 18 to 55 years who received the vaccine reported pain that either interfered with daily activity or prevented it; the percentage of patients reporting this degree of pain (15.2% to 18.5%) was lower in patients 56 years and older. The largest difference occurred in the incidence of redness in patients 56 years and older (7.2% after dose 2, 4.7% after dose 1).[66080] After Moderna COVID-19 vaccine administration, pain at the injection site was reported in 92% of patients. The highest rates of pain were in patients 18 to 64 years after dose 2, with 89.9% reporting pain and 4.6% reporting that it prevented daily activity and required the use of pain relievers. Erythema or redness (8.9% after dose 2, 3% after dose 1) and swelling or hardness (12.6% after dose 2, 6.7% after dose 1) were reported in patients 18 to 64 years. Similar numbers of erythema or redness (7.5% after dose 2, 2.3% after dose 1) and swelling or hardness (10.8% after dose 2, 4.4% after dose 1) were reported in patients 65 years and older. Axillary swelling or tenderness was more common after the second dose in both age groups (18 to 64 years: 16.2% after dose 2, 11.6% after dose 1 and 65 years and older: 8.5% after dose 2, 6.1% after dose 1). Most local reactions lasted 1 to 3 days. Delayed reactions, occurring 8 or more days after administration, occurred in 0.8% and 0.2% of patients after the first and second dose, respectively, and usually resolved over 4 to 5 days.[66120] [66199] Patients who have received dermal fillers may develop swelling at or near the site of filler injection (usually face or lips) after mRNA COVID-19 vaccine administration. It appears to be temporary and can resolve with medical treatment, including corticosteroid therapy. These patients may receive mRNA COVID-19 vaccines without additional precautions; however, they should be advised to contact their health care provider if they develop swelling at or near the site of dermal filler after vaccination.[66175]

During clinical trials, fatigue (62.9% to 70%), headache (55.1% to 64.7%), and malaise (0.5%) occurred after administration of the COVID-19 vaccine. The rates and severity of the reactions were generally higher after the second dose compared to the first dose.[66080] [66120] In patients 18 to 55 years of age who received the Pfizer-BioNTech COVID-19 vaccine, moderate fatigue (causing some interference with activity) was reported in majority of patients experiencing fatigue (33.7% after dose 2, 19.9% after dose 1). In patients 56 years and older, moderate fatigue was also reported by more patients after the second dose (26.6% after dose 2, 13.3% after dose 1). Headache was more common after the second dose in both age groups (18 to 55 years: 51.7% after dose 2, 41.9% after dose 1 and 56 years and older: 39% after dose 2, 25.2% after dose 1).[66080] In Moderna COVID-19 vaccine clinical trials, fatigue (70%) was the most frequently reported systemic adverse reaction. The highest incidence of fatigue was reported by patients 18 to 64 years after the second dose, with 67.6% reporting any fatigue, 10.7% reporting fatigue that prevented daily activities, and 1 patient reporting fatigue that required an emergency room visit or hospitalization. Headache was more common after the second dose in both age groups (18 to 64 years: 62.8% after dose 2, 35.3% after dose 1 and 65 years and older: 46.2% after dose 2, 24.5% after dose 1).[66120]

Musculoskeletal adverse reactions reported during COVID-19 vaccine clinical trials include muscle pain or myalgia (38.3% to 61.5%) and/or joint pain or arthralgia (23.6% to 46.4%).[66080] [66120] In patients 18 to 55 years of age, new or worsened muscle pain was reported in about one-third of patients (37.3%) after the second Pfizer-BioNTech COVID-19 vaccine dose compared to 21.3% after the first dose. A similar number of patients 56 years or older reported new or worsened muscle pain (28.7% after dose 2, 13.9% after dose 1). Moderate to severe muscle pain (causing some interference with daily activities or preventing activities) was reported after dose 2 in 21.7% of patients 18 to 55 years and 16.6% of patients 56 years and older. New or worsened joint pain was reported in approximately twice as many patients after the second dose compared to the first dose in both age groups (18 to 55 years: 21.9% after dose 2, 11% after dose 1 and 56 years and older: 18.9% after dose 2, 8.6% after dose 1).[66080] During Moderna COVID-19 clinical trials, myalgia was more common after the second dose in both age groups (18 to 64 years: 61.6% after dose 2, 23.7% after dose 1 and 65 years and older: 47.1% after dose 2, 19.7% after dose 1). Myalgia that prevented daily activity was reported in significantly more patients after the second dose (18 to 64 years: 10.1% after dose 2, 0.6% after dose 1 and 65 years and older: 5.6% after dose 2, 0.5% after dose 1). Similar to myalgia, arthralgia was more common after the second dose in both age groups (18 to 64 years: 45.5% after dose 2, 16.6% after dose 1 and 65 years and older: 35% after dose 2, 16.4% after dose 1). Arthralgia that prevented daily activity was reported in significantly more patients after the second dose (18 to 64 years: 5.9% after dose 2, 0.4% after dose 1 and 65 years and older: 3.3% after dose 2, 0.3% after dose 1). One case of arthralgia requiring an emergency room visit or hospitalization was reported in the vaccine group.[66120]

Diarrhea, nausea, and vomiting were reported during COVID-19 vaccine clinical trials.[66080] [66120] During clinical trials in patients 16 years and older, nausea (1.1%) was reported after administration of the Pfizer-BioNTech COVID-19 vaccine. Diarrhea was reported by 10.4% to 11.1% of patients 18 to 55 years and 8.3% of patients 56 years and older. Vomiting was reported in 1.2% to 1.9% of patients 18 to 55 years and 0.5% to 0.7% of patients 56 years and older.[66080] During Moderna COVID-19 vaccine clinical trials, nausea and/or vomiting was reported in twice as many patients 18 to 64 years after dose 2 (21.4%) compared to dose 1 (9.4%). A similar difference was seen in patients 65 years and older (11.8% after dose 2; 5.2% after dose 1). One case of intractable nausea and vomiting requiring hospitalization was reported as a serious adverse reaction in the vaccine group.[66120]

Lymphadenopathy was reported in 0.3% of patients 16 years and older during Pfizer-BioNTech COVID-19 vaccine clinical trials. From dose 1 through 20 days after dose 2, lymphadenopathy was reported in more patients in the vaccine group (n = 64) than in the placebo group (n = 6).[66080] During Moderna COVID-19 vaccine clinical trials, lymphadenopathy-related events were reported in 1.1% of patients who received the vaccine compared to 0.6% of patients who received placebo. These events included lymphadenopathy, lymphadenitis, lymph node pain, vaccination-site lymphadenopathy, injection-site lymphadenopathy, and axillary mass.[66120]

Serious allergic reactions or anaphylactoid reactions have been reported in patients outside of clinical trials during mass vaccination. During phase 2/3 Pfizer-BioNTech COVID-19 vaccine clinical trials, a subset of patients in the vaccinated group had hypersensitivity-related adverse reactions, possibly representing allergic reactions (0.63% vs. 0.51%, placebo).[66080] [66175] During mass vaccination with the Pfizer-BioNTech COVID-19 vaccine outside of clinical trials, severe allergic reactions, including anaphylaxis and other hypersensitivity reactions (e.g. rash, pruritus, urticaria, angioedema), have been reported.[66080] During this time, 21 cases of anaphylaxis were identified (a rate of 11.1 anaphylaxis cases per million doses administered). Of those, 17 patients had a documented history of allergies or allergic reaction and 7 patients had a history of anaphylaxis. Median time to symptom onset was 13 minutes (range = 2 to 150 minutes). Twenty patients were available for follow-up and all had recovered or been discharged home. An additional 83 nonanaphylaxis allergic reactions were reported; symptoms included pruritus, rash, itchy and scratchy sensation in the throat, and mild respiratory symptoms. Median time to symptom onset was 12 minutes (range = less than 1 minute to 20 hours). In most patients (85%), symptoms occurred within 30 minutes. For 67% of patients, a past history of allergies or allergic reactions was documented.[66397] During Moderna COVID-19 clinical trials, hypersensitivity related adverse reactions were reported in 1.5% of vaccine recipients compared to 1.1% of placebo recipients. Hypersensitivity reactions included injection site rash and injection site urticaria.[66120] During mass vaccination with the Moderna vaccine, 10 cases of anaphylaxis were identified (a rate of 2.5 anaphylaxis cases per million doses administered). Of those, 9 patients had a documented history of allergies or allergic reaction and 5 patients had a history of anaphylaxis. Median time to symptom onset was 7.5 minutes (range = 1 to 45 minutes). Eight patients were available for follow-up and all had recovered or been discharged home. An additional 43 nonanaphylaxis allergic reactions were reported; symptoms included pruritus, rash, itchy and scratchy sensation in the throat, sensations of throat closure, and mild respiratory symptoms. Median time to symptom onset was 15 minutes (range = less than 1 minute to 24 hours). In most patients (73%), symptoms occurred within 30 minutes. For 60% of patients, a past history of allergies or allergic reactions was documented.[66398]

During Pfizer-BioNTech COVID-19 vaccine clinical trials, appendicitis was reported as a serious adverse reaction in 8 patients receiving vaccine (n = 18,801) vs. 4 receiving placebo (n = 18,785). Bell's palsy (facial paralysis) was reported by 4 patients in the Pfizer-BioNTech COVID-19 vaccine group (n = 18,801) compared to none of the patients in the placebo group. Onset of facial paralysis occurred on day 37 after dose 1 (patient did not receive dose 2) and days 3, 9, and 48 after dose 2. During Moderna COVID-19 vaccine clinical trials, there were 3 reports of Bell's palsy in the vaccine group (n = 15,185) compared to 1 patient in the placebo group (n = 15,166). Onset of facial paralysis occurred 22, 28, and 32 days after vaccination in the vaccine group and 17 days after vaccination in the placebo group. In the United States, it is estimated that between 25 and 35 in 100,000 people are affected with Bell's palsy. Currently available information is insufficient to determine a causal relationship between appendicitis or Bell's palsy with the vaccine.[66080] [66120] [66184]

During clinical trials, chills (31.9% to 45.4%) and fever (14.2% to 15.5%) occurred after administration of the COVID-19 vaccine. The rates and severity of the reactions were generally higher after the second dose compared to the first dose.[66080] [66120] In patients 18 to 55 years, fever of 101.2 degrees F (38.4 degrees C) or higher was reported in 6 times more patients after the second Pfizer-BioNTech COVID-19 vaccine dose (6.4% after dose 2, 1% after dose 1). In patients 56 years and older, fever of 101.2 degrees F (38.4 degrees C) or higher was reported in 3% of patients after dose 2 compared to 0.3% of patients after dose 1. In patients 18 to 55 years old, chills were reported by more patients after the second Pfizer-BioNTech COVID-19 vaccine dose (35.1% after dose 2, 14% after dose 1). A similar difference in the incidence of chills was seen in patients 56 years and older (22.7% after dose 2, 6.3% after dose 1).[66080] After Moderna COVID-19 vaccine administration, fever was reported in more patients 18 to 64 years after dose 2 (17.4%) compared to dose 1 (0.9%). A fever of 102.1 degrees F (38.9 degrees C) or higher was reported by 1.7% of patients after dose 2 compared to less than 0.1% after dose 1. Significantly more patients 65 years and older also reported fever after the second dose (10% after dose 1, 0.3% after dose 2). A fever of 102.1 degrees F (38.9 degrees C) or higher was reported by 0.5% of patients after dose 2 compared to less than 0.1% after dose 1. The greatest incidence of chills occurred after dose 2 in patients 18 to 64 years (48.6%).[66120]

Immunocompromised patients, including patients with immunosuppression or receiving immunosuppressive therapy, may not have an adequate immune response to the COVID-19 vaccine.[66080] [66120] Counsel patients about the unknown vaccine safety profile and effectiveness in immunocompromised patients, the potential for reduced immune responses, and the need to continue following precautions to avoid exposure to the SARS-CoV-2 virus.[66175] Immunosuppressed persons may include patients with severe combined immunodeficiency (SCID), hypogammaglobulinemia, agammaglobulinemia, or an immune system compromised by drug therapy (i.e., corticosteroid therapy with greater than physiologic doses). Short-term (less than 2 weeks) corticosteroid therapy or intra-articular, bursal, or tendon injections with corticosteroids should not be immunosuppressive.[65107] Ideally, COVID-19 vaccination should be completed at least 2 weeks before initiation of immunosuppressive therapies. When it is not possible to administer the COVID-19 vaccine in advance, people on immunosuppressive therapy can still receive COVID-19 vaccination. Antibody testing is not recommended to assess for immunity after COVID-19 vaccination. Re-vaccination is not recommended after immune competence is regained in patients who received mRNA COVID-19 vaccines during treatment with immunosuppressive drugs. For patients receiving antibody therapies not specific to COVID-19 treatment (e.g., intravenous immunoglobulin, RhoGAM), there is no recommended minimum interval between these therapies and administration of mRNA COVID-19 vaccines. Administration of mRNA COVID-19 vaccines either together or at any interval before or after receipt of an antibody-containing product is unlikely to substantially impair the development of a protective antibody response.[66175]

Patients with altered immune states due to generalized neoplastic disease or an immune system compromised by radiation therapy or chemotherapy may not have an adequate immune response to the COVID-19 vaccine.[65107] [66080] [66120] Counsel patients about the unknown vaccine safety profile and effectiveness in immunocompromised patients, the potential for reduced immune responses, and the need to continue following precautions to avoid exposure to the SARS-CoV-2 virus. Antibody testing is not recommended to assess for immunity after COVID-19 vaccination. Re-vaccination is not recommended after immune competence is regained in patients who received mRNA COVID-19 vaccines during chemotherapy or treatment with other immunosuppressive drugs.[66175] Vaccination should be delayed for at least 3 months after hematopoietic cell transplantation (HCT) or engineered cellular therapy (e.g. CAR-T cells) to maximize vaccine efficacy. For patients with hematologic malignancies receiving intensive cytotoxic chemotherapy (e.g., cytarabine/anthracycline-based induction regimens for AML), delay vaccination until absolute neutrophile count (ANC) recovery. For patients with solid tumor malignancies undergoing major surgery, separate date of surgery from vaccination by at least a few days to allow symptoms (e.g. fever) to be correctly attributed to surgery vs. vaccination. For more complex surgeries (e.g. splenectomy or surgery that may lead to an immunosuppressive state) surgeons may recommend a wider window (+/- 2 weeks) from the time of surgery.[66335]

Postponing vaccination with the COVID-19 vaccine is recommended in patients with an acute moderate to severe illness or infection, both before the first vaccine or before the second vaccine if infection develops after the first vaccine administration. Patients who have active tuberculosis (TB) disease or an illness that is being evaluated as active TB disease can receive an mRNA COVID-19 vaccine. If vaccination is not deferred, observe the patient for 15 minutes after vaccine administration.[66175]

Clinical trials for the vaccine were expanded to include patients with chronic, stable human immunodeficiency virus (HIV) infection. Efficacy information for the COVID-19 vaccine is not yet available in this patient population and although patients with HIV infection or acquired immunodeficiency syndrome (AIDS) could have a diminished response, the COVID-19 vaccine should be offered to patients with chronic, stable HIV.[65107] [66080] [66086] [66120] Counsel patients about the unknown vaccine safety profile and effectiveness in immunocompromised patients, the potential for reduced immune responses, and the need to continue following precautions to avoid exposure to the SARS-CoV-2 virus. When vaccinating immunocompromised patients, observe patients for 15 minutes after vaccine administration.[66175]

The COVID-19 vaccine is administered by intramuscular (IM) injection only. Carefully consider the risks and benefits in patients at increased risk for bleeding after an intramuscular injection, such as thrombocytopenia, bleeding disorders (e.g., hemophilia), coagulopathy, vitamin K deficiency, and those receiving anticoagulant therapy. Caution and appropriate precautions to minimize the risk of bleeding or hematoma formation are advised.[65107] [66080] [66120]

Available data are insufficient to inform vaccine-associated risks during pregnancy. It is unknown whether administration of the COVID-19 vaccine can cause fetal harm or affect the reproductive system.[66080] [66120] The American College of Obstetricians and Gynecologists (ACOG) recommends that women eligible for the COVID-19 vaccine be offered the vaccine regardless of pregnancy status. Women planning to become pregnant who are eligible for the COVID-19 vaccine are encouraged to complete their vaccination series prior to conception to ensure maximal protection prior to pregnancy. If a woman becomes pregnant after the first dose, administer the second dose as indicated. If a woman becomes pregnant within 30 days of receipt of the vaccine, encourage participation in the CDC's V-SAFE program.[66179] There are no recommendations for routine pregnancy testing before COVID-19 vaccination. Patients who are trying to become pregnant do not need to avoid pregnancy after COVID-19 vaccination. There is no evidence that any of the COVID-19 vaccines affect future fertility.[66175] In a prospective cohort study of 131 mRNA COVID-19 vaccine recipients (84 pregnant, 31 lactating, and 16 non-pregnant), vaccine-induced antibody titers were equivalent in pregnant and lactating women compared to non-pregnant women. All titers were significantly higher than those induced during SARS-CoV-2 infection during pregnancy. Vaccine-generated antibodies were present in all umbilical cord blood samples; neutralizing antibody titers were lower in umbilical cord compared to maternal sera, although statistical significance was not reached. No differences in reactogenicity were noted between the groups.[66558] A pregnancy exposure registry is available that monitors pregnancy outcomes in women exposed to Moderna COVID-19 vaccine during pregnancy. Encourage women vaccinated with Moderna COVID-19 vaccine to enroll in the registry by calling 1-866-663-3762.[66120] In developmental toxicity studies, when the same quantity of mRNA and other ingredients included in a single human dose of Moderna (100 mcg mRNA) and Pfizer-BioNTech (30 mcg mRNA) COVID-19 vaccines were administered to female rats by the IM route on 4 occasions, no vaccine-related adverse effects on female fertility, fetal development, or postnatal development were reported.[66080] [66120]

There are no data regarding use of the COVID-19 vaccine during breast-feeding and its excretion in human breast milk is unknown.[66080] [66120] The American College of Obstetricians and Gynecologists (ACOG) recommends that breast-feeding women eligible for the COVID-19 vaccine be offered the vaccine.[66179] In a prospective cohort study of 131 mRNA COVID-19 vaccine recipients (84 pregnant, 31 lactating, and 16 non-pregnant), vaccine-induced antibody titers were equivalent in pregnant and lactating women compared to non-pregnant women. All titers were significantly higher than those induced during SARS-CoV-2 infection during pregnancy. Vaccine-generated antibodies were present in all breastmilk samples. No differences in reactogenicity were noted between the groups.[66558] If a breast-feeding infant experiences an adverse event possibly related to a maternally administered vaccine, health care providers are encouraged to report the adverse event to the FDA.[66080]