trastuzumab
Dosage Form: injection
FULL PRESCRIBING INFORMATION
Cardiomyopathy
Herceptin administration can result in sub‑clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline‑containing chemotherapy regimens.
Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function. [see Warnings and Precautions (5.1) and Dosage and Administration (2.2)]
Infusion Reactions; Pulmonary Toxicity
Herceptin administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of Herceptin administration. Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. [see Warnings and Precautions (5.2, 5.4)]
Embryo Fetal Toxicity
Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)]
Indications and Usage for Herceptin
Adjuvant Breast Cancer
Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies (14.1)]) breast cancer
- as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
- with docetaxel and carboplatin
- as a single agent following multi-modality anthracycline based therapy.
Metastatic Breast Cancer
Herceptin is indicated:
- In combination with paclitaxel for first‑line treatment of HER2‑overexpressing metastatic breast cancer
- As a single agent for treatment of HER2‑overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.
Metastatic Gastric Cancer
Herceptin is indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease.
Herceptin Dosage and Administration
Recommended Doses and Schedules
Do not administer as an intravenous push or bolus. Do not mix Herceptin with other drugs.
Adjuvant Treatment, Breast Cancer:
Administer according to one of the following doses and schedules for a total of 52 weeks of Herceptin therapy:
During and following paclitaxel, docetaxel, or docetaxel/carboplatin:
- Initial dose of 4 mg/kg as an intravenous infusion over 90 minutes then at 2 mg/kg as an intravenous infusion over 30 minutes weekly during chemotherapy for the first 12 weeks (paclitaxel or docetaxel) or 18 weeks (docetaxel/carboplatin).
- One week following the last weekly dose of Herceptin, administer Herceptin at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks.
As a single agent within three weeks following completion of multi‑modality, anthracycline‑based chemotherapy regimens:
- Initial dose at 8 mg/kg as an intravenous infusion over 90 minutes
- Subsequent doses at 6 mg/kg as an intravenous infusion over 30–90 minutes every three weeks.
[see Dose Modifications (2.2)]
Metastatic Treatment, Breast Cancer:
- Administer Herceptin, alone or in combination with paclitaxel, at an initial dose of 4 mg/kg as a 90 minute intravenous infusion followed by subsequent once weekly doses of 2 mg/kg as 30 minute intravenous infusions until disease progression.
Metastatic Gastric Cancer
- Administer Herceptin at an initial dose of 8 mg/kg as a 90 minute intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30-90 minutes every three weeks until disease progression [see Dose Modifications (2.2)].
Dose Modifications
Infusion Reactions
[see Boxed Warning, Warnings and Precautions (5.2)]
- Decrease the rate of infusion for mild or moderate infusion reactions
- Interrupt the infusion in patients with dyspnea or clinically significant hypotension
- Discontinue Herceptin for severe or life‑threatening infusion reactions.
Cardiomyopathy
[see Boxed Warning, Warnings and Precautions (5.1)]
Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin and at regular intervals during treatment. Withhold Herceptin dosing for at least 4 weeks for either of the following:
- ≥ 16% absolute decrease in LVEF from pre‑treatment values
- LVEF below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values.
Herceptin may be resumed if, within 4–8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤ 15%.
Permanently discontinue Herceptin for a persistent ( > 8 weeks) LVEF decline or for suspension of Herceptin dosing on more than 3 occasions for cardiomyopathy.
Preparation for Administration
Reconstitution
Reconstitute each 440 mg vial of Herceptin with 20 mL of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative to yield a multi‑dose solution containing 21 mg/mL trastuzumab. In patients with known hypersensitivity to benzyl alcohol, reconstitute with 20 mL of Sterile Water for Injection (SWFI) without preservative to yield a single use solution.
Use appropriate aseptic technique when performing the following reconstitution steps:
- Using a sterile syringe, slowly inject the 20 mL of diluent into the vial containing the lyophilized cake of Herceptin. The stream of diluent should be directed into the lyophilized cake.
- Swirl the vial gently to aid reconstitution. DO NOT SHAKE.
- Slight foaming of the product may be present upon reconstitution. Allow the vial to stand undisturbed for approximately 5 minutes.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect visually for particulates and discoloration. The solution should be free of visible particulates, clear to slightly opalescent and colorless to pale yellow.
- Store reconstituted Herceptin at 2–8° C; discard unused Herceptin after 28 days. If Herceptin is reconstituted with SWFI without preservative, use immediately and discard any unused portion.
Dilution
- Determine the dose (mg) of Herceptin [see Dosage and Administration (2.1)]. Calculate the volume of the 21 mg/mL reconstituted Herceptin solution needed, withdraw this amount from the vial and add it to an infusion bag containing 250 mL of 0.9% Sodium Chloride Injection, USP.
DO NOT USE DEXTROSE (5%) SOLUTION. - Gently invert the bag to mix the solution.
Dosage Forms and Strengths
440 mg lyophilized powder per multi‑use vial.
Contraindications
None.
Warnings and Precautions
Cardiomyopathy
Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy]. Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF).
There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline.
Withhold Herceptin for ≥ 16% absolute decrease in LVEF from pre‑treatment values or an LVEF value below institutional limits of normal and ≥ 10% absolute decrease in LVEF from pretreatment values [see Dosage and Administration (2.2)]. The safety of continuation or resumption of Herceptin in patients with Herceptin‑induced left ventricular cardiac dysfunction has not been studied.
Cardiac Monitoring
Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
- Baseline LVEF measurement immediately prior to initiation of Herceptin
- LVEF measurements every 3 months during and upon completion of Herceptin
- Repeat LVEF measurement at 4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [ see Dosage and Administration (2.2)]
- LVEF measurements every 6 months for at least 2 years following completion of Herceptin as a component of adjuvant therapy.
In Study 1, 16% (136/844) of patients discontinued Herceptin due to clinical evidence of myocardial dysfunction or significant decline in LVEF. In Study 3, the number of patients who discontinued Herceptin due to cardiac toxicity was 2.6% (44/1678). In Study 4, a total of 2.9% (31/1056) patients in the TCH arm (1.5% during the chemotherapy phase and 1.4% during the monotherapy phase) and 5.7% (61/1068) patients in the AC‑TH arm (1.5% during the chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity.
Among 32 patients receiving adjuvant chemotherapy (Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy and all other patients were receiving cardiac medication at last follow‑up. Approximately half of the surviving patients had recovery to a normal LVEF (defined as ≥50%) on continuing medical management at the time of last follow‑up. Incidence of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin in patients with Herceptin‑induced left ventricular cardiac dysfunction has not been studied.
| Incidence of CHF | |||
| Study | Regimen | Herceptin | Control |
| |||
| 1 & 2* | AC† → Paclitaxel+Herceptin | 2% (32/1677) | 0.4% (7/1600) |
| 3 | Chemo → Herceptin | 2% (30/1678) | 0.3% (5/1708) |
| 4 | AC† → Docetaxel+Herceptin | 2% (20/1068) | 0.3% (3/1050) |
| 4 | Docetaxel+Carbo+Herceptin | 0.4% (4/1056) | 0.3% (3/1050) |
| Incidence | |||||
| NYHA I‑IV | NYHA III‑IV | ||||
| Study | Event | Herceptin | Control | Herceptin | Control |
| |||||
| 5 (AC)† | Cardiac Dysfunction | 28% | 7% | 19% | 3% |
| 5 (paclitaxel) | Cardiac Dysfunction | 11% | 1% | 4% | 1% |
| 6 | Cardiac Dysfunction‡ | 7% | N/A | 5% | N/A |
In Study 4, the incidence of NCI‑CTC Grade 3/4 cardiac ischemia/infarction was higher in the Herceptin containing regimens: (AC‑TH: 0.3% (3/1068) and TCH 0.2% (: 2/1056)) as compared to none in AC‑T.
Infusion Reactions
Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia. [see Adverse Reactions (6.1)]
In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable including progressive worsening, initial improvement followed by clinical deterioration, or delayed post‑infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction.
Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions.
There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion reaction were pre‑medicated with antihistamines and/or corticosteroids. While some patients tolerated Herceptin infusions, others had recurrent severe infusion reactions despite pre‑medications.
Embryo-Fetal Toxicity
Herceptin can cause fetal harm when administered to a pregnant woman. In post marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy and provide contraception counseling to women of childbearing potential. [see Use in Specific Populations (8.1), Patient Counseling Information (17)].
Pulmonary Toxicity
Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non‑cardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions (5.2)]. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.
Exacerbation of Chemotherapy-Induced Neutropenia
In randomized, controlled clinical trials the per‑patient incidences of NCI CTC Grade 3–4 neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received Herceptin and those who did not. [see Adverse Reactions (6.1)]
HER2 Testing
Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown. Due to differences in tumor histopathology, use FDA-approved tests for the specific tumor type (breast or gastric/gastroesophageal adenocarcinoma) to assess HER2 protein overexpression and HER2 gene amplification. Tests should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
Several FDA‑approved commercial assays are available to aid in the selection of breast cancer and metastatic gastric cancer patients for Herceptin therapy. Users should refer to the package inserts of specific assay kits for information on the Intended Use, and the validation and performance of each assay.
Limitations in assay precision make it inadvisable to rely on a single method to rule out potential Herceptin benefit.
Treatment outcomes for adjuvant breast cancer (Studies 2 and 3) and for metastatic breast cancer (Study 5) as a function of IHC and FISH testing are provided in Tables 8 and 10.
Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers. Study 7 demonstrated that gene amplification and protein overexpression were not as well correlated as with breast cancer. Treatment outcomes for metastatic gastric cancer (Study 7), based on HER2 gene amplification (FISH) and HER2 protein overexpression (IHC) test results are provided in Table 12.
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the label:
- Cardiomyopathy [see Warnings and Precautions (5.1)]
- Infusion reactions [see Warnings and Precautions (5.2)]
- Embryo-fetal Toxicity [see Warnings and Precautions (5.3)]
- Pulmonary toxicity [see Warnings and Precautions (5.4)]
- Exacerbation of chemotherapy‑induced neutropenia [see Warnings and Precautions (5.5)]
The most common adverse reactions in patients receiving Herceptin in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia. Adverse reactions requiring interruption or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration (2.2)].
In the metastatic gastric cancer setting, the most common adverse reactions (≥ 10%) that were increased (≥ 5% difference) in the Herceptin arm as compared to the chemotherapy alone arm were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common adverse reactions which resulted in discontinuation of treatment on the Herceptin-containing arm in the absence of disease progression were infection, diarrhea, and febrile neutropenia.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adjuvant Breast Cancer Studies
The data below reflect exposure to Herceptin across three randomized, open‑label studies, Studies 1, 2, and 3, with (n= 3355) or without (n= 3308) trastuzumab in the adjuvant treatment of breast cancer.
The data summarized in Table 3 below, from Study 3, reflect exposure to Herceptin in 1678 patients; the median treatment duration was 51 weeks and median number of infusions was 18. Among the 3386 patients enrolled in Study 3, the median age was 49 years (range: 21 to 80 years), 83% of patients were Caucasian, and 13% were Asian.
| 1 Year Herceptin | Observation | |
| Adverse Reaction | (n=1678) | (n=1708) |
| ||
Cardiac | ||
| Hypertension | 64 (4%) | 35 (2%) |
| Dizziness | 60 (4%) | 29 (2%) |
| Ejection Fraction Decreased | 58 (3.5%) | 11 (0.6%) |
| Palpitations | 48 (3%) | 12 (0.7%) |
| Cardiac Arrhythmias† | 40 (3%) | 17 (1%) |
| Cardiac Failure Congestive | 30 (2%) | 5 (0.3%) |
| Cardiac Failure | 9 (0.5%) | 4 (0.2%) |
| Cardiac Disorder | 5 (0.3%) | 0 (0%) |
| Ventricular Dysfunction | 4 (0.2%) | 0 (0%) |
Respiratory Thoracic Mediastinal Disorders | ||
| Cough | 81 (5%) | 34 (2%) |
| Influenza | 70 (4%) | 9 (0.5%) |
| Dyspnea | 57 (3%) | 26 (2%) |
| URI | 46 (3%) | 20 (1%) |
| Rhinitis | 36 (2%) | 6 (0.4%) |
| Pharyngolaryngeal Pain | 32 (2%) | 8 (0.5%) |
| Sinusitis | 26 (2%) | 5 (0.3%) |
| Epistaxis | 25 (2%) | 1 (0.06%) |
| Pulmonary Hypertension | 4 (0.2%) | 0 (0%) |
| Interstitial Pneumonitis | 4 (0.2%) | 0 (0%) |
Gastrointestinal Disorders | ||
| Diarrhea | 123 (7%) | 16 (1%) |
| Nausea | 108 (6%) | 19 (1%) |
| Vomiting | 58 (3.5%) | 10 (0.6%) |
| Constipation | 33 (2%) | 17 (1%) |
| Dyspepsia | 30 (2%) | 9 (0.5%) |
| Upper Abdominal Pain | 29 (2%) | 15 (1%) |
Musculoskeletal & Connective Tissue Disorders | ||
| Arthralgia | 137 (8%) | 98 (6%) |
| Back Pain | 91 (5%) | 58 (3%) |
| Myalgia | 63 (4%) | 17 (1%) |
| Bone Pain | 49 (3%) | 26 (2%) |
| Muscle Spasm | 46 (3%) | 3 (0.2%) |
Nervous System Disorders | ||
| Headache | 162 (10%) | 49 (3%) |
| Paraesthesia | 29 (2%) | 11 (0.6%) |
Skin & Subcutaneous Tissue Disorders | ||
| Rash | 70 (4%) | 10 (0.6%) |
| Nail Disorders | 43 (2%) | 0 (0%) |
| Pruritis | 40 (2%) | 10 (0.6%) |
General disorders | ||
| Pyrexia | 100 (6%) | 6 (0.4%) |
| Edema Peripheral | 79 (5%) | 37 (2%) |
| Chills | 85 (5%) | 0 (0%) |
| Aesthenia | 75 (4.5%) | 30 (2%) |
| Influenza‑like Illness | 40 (2%) | 3 (0.2%) |
| Sudden Death | 1 (0.06%) | 0 (0%) |
Infections | ||
| Nasopharyngitis | 135 (8%) | 43 (3%) |
| UTI | 39 (3%) | 13 (0.8%) |
Immune System Disorders | ||
| Hypersensitivity | 10 (0.6%) | 1 (0.06%) |
| Autoimmune Thyroiditis | 4 (0.3%) | 0 (0%) |
The data from Studies 1 and 2 were obtained from 3206 patients, of whom 1635 received Herceptin; the median treatment duration was 50 weeks. The median age was 49 years (range: 24–80); 84% of patients were White, 7% Black, 4% Hispanic, and 4% Asian.
In Study 1, only Grade 3–5 adverse events, treatment‑related Grade 2 events, and Grade 2–5 dyspnea were collected during and for up to 3 months following protocol‑specified treatment. The following non‑cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (31% vs. 28%), fatigue (28% vs. 22%), infection (22% vs. 14%), hot flashes (17% vs. 15%), anemia (13% vs. 7%), dyspnea (12% vs. 4%), rash/desquamation (11% vs. 7%), neutropenia (7% vs. 5%), headache (6% vs. 4%), and insomnia (3.7% vs. 1.5%). The majority of these events were Grade 2 in severity.
In Study 2, data collection was limited to the following investigator‑attributed treatment‑related adverse reactions NCI‑CTC Grade 4 and 5 hematologic toxicities, Grade 3–5 non‑hematologic toxicities, selected Grade 2–5 toxicities associated with taxanes (myalgia, arthralgias, nail changes, motor neuropathy, sensory neuropathy) and Grade 1–5 cardiac toxicities occurring during chemotherapy and/or Herceptin treatment. The following non‑cardiac adverse reactions of Grade 2–5 occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (11% vs. 8.4%), myalgia (10% vs. 8%), nail changes (9% vs. 7%), and dyspnea (2.5% vs. 0.1%). The majority of these events were Grade 2 in severity.
Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose of study treatment [AC‑TH: n = 1068; TCH: n = 1056]. The overall median treatment duration was 54 weeks in both the AC‑TH and TCH arms. The median number of infusions was 26 in the AC‑TH arm and 30 in the TCH arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy period. Among these patients, the median age was 49 years (range 22 to 74 years). In Study 4, the toxicity profile was similar to that reported in Studies 1, 2, and 3 with the exception of a low incidence of CHF in the TCH arm.
Metastatic Breast Cancer Studies
The data below reflect exposure to Herceptin in one randomized, open‑label study, Study 5, of chemotherapy with (n=235) or without (n=234) trastuzumab in patients with metastatic breast cancer, and one single‑arm study (Study 6; n=222) in patients with metastatic breast cancer. Data in Table 4 are based on Studies 5 and 6.
Among the 464 patients treated in Study 5, the median age was 52 years (range: 25–77 years). Eighty‑nine percent were White, 5% Black, 1% Asian and 5% other racial/ethnic groups. All patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for ≥ 6 months and ≥ 12 months were 58% and 9%, respectively.
Among the 352 patients treated in single agent studies (213 patients from Study 6), the median age was 50 years (range 28–86 years), 86% were White, 3% were Black, 3% were Asian, and 8% in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for ≥ 6 months and ≥ 12 months were 31% and 16%, respectively.
| Single Agent* n = 352 | Herceptin + Paclitaxel n = 91 | Paclitaxel Alone n = 95 | Herceptin + AC† n = 143 | AC† Alone n = 135 | ||
| ||||||
| Body as a Whole | ||||||
| Pain | 47% | 61% | 62% | 57% | 42% | |
| Asthenia | 42% | 62% | 57% | 54% | 55% | |
| Fever | 36% | 49% | 23% | 56% | 34% | |
| Chills | 32% | 41% | 4% | 35% | 11% | |
| Headache | 26% | 36% | 28% | 44% | 31% | |
| Abdominal pain | 22% | 34% | 22% | 23% | 18% | |
| Back pain | 22% | 34% | 30% | 27% | 15% | |
| Infection | 20% | 47% | 27% | 47% | 31% | |
| Flu syndrome | 10% | 12% | 5% | 12% | 6% | |
| Accidental injury | 6% | 13% | 3% | 9% | 4% | |
| Allergic reaction | 3% | 8% | 2% | 4% | 2% | |
| Cardiovascular | ||||||
| Tachycardia | 5% | 12% | 4% | 10% | 5% | |
| Congestive heart failure | 7% | 11% | 1% | 28% | 7% | |
| Digestive | ||||||
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