BAVENCIO (Page 3 of 7)

5.2 Infusion-Related Reactions

BAVENCIO can cause severe or life-threatening infusion-related reactions [see Adverse Reactions (6.1)]. Premedicate with antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop the infusion and permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

Infusion-related reactions occurred in 25% of patients treated with BAVENCIO including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Ninety-three percent of patients received premedication with antihistamine and acetaminophen. Eleven (92%) of the 12 patients with Grade ≥ 3 reactions were treated with intravenous corticosteroids. Fourteen percent of patients had infusion-related reactions that occurred after the BAVENCIO infusion was completed.

5.3 Complications of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT.

5.4 Major Adverse Cardiovascular Events (MACE)

BAVENCIO in combination with axitinib can cause severe and fatal cardiovascular events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events.

MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib in a randomized trial, JAVELIN Renal 101. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%). Median time to onset of MACE was 4.2 months (range: 2 days to 24.5 months).

5.5 Embryo-Fetal Toxicity

Based on its mechanism of action, BAVENCIO can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking BAVENCIO, inform the patient of the potential risk to a fetus. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least one month after the last dose of BAVENCIO [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

6.1 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.

The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to BAVENCIO 10 mg/kg intravenously every 2 weeks as a single agent in 1738 patients enrolled in the JAVELIN Merkel 200 and JAVELIN Solid Tumor trials and to BAVENCIO 10 mg/kg intravenously every 2 weeks in combination with axitinib 5 mg orally twice daily in 489 patients enrolled in the JAVELIN Renal 100 and JAVELIN Renal 101 trials. In the BAVENCIO monotherapy population, 24% of patients were exposed for ≥ 6 months and 7% were exposed for ≥ 12 months. The population characteristics of BAVENCIO in combination with axitinib are shown below. When BAVENCIO was used in combination with axitinib, 70% of patients were exposed for ≥ 6 months and 31% were exposed for ≥ 12 months. The following criteria were used to classify an adverse reaction as immune-mediated: onset within 90 days after last dose of BAVENCIO, no spontaneous resolution within 7 days of onset, treatment with corticosteroids or other immunosuppressant or hormone replacement therapy, biopsy consistent with immune-mediated reaction, and no other clear etiology.

Metastatic Merkel Cell Carcinoma

The data described below reflect exposure to BAVENCIO 10 mg/kg intravenously every 2 weeks in 88 patients with metastatic MCC enrolled in the JAVELIN Merkel 200 trial. Patients with any of the following were excluded: autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogeneic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; central nervous system (CNS) metastases; infection with HIV, hepatitis B, or hepatitis C; or ECOG performance score ≥ 2.

The median duration of exposure to BAVENCIO was 4 months (range: 2 weeks to 21 months). Forty percent of patients received BAVENCIO for more than 6 months and 14% were treated for more than one year [see Clinical Studies (14.1)]. The study population characteristics were: median age of 73 years (range: 33 to 88), 74% male, 92% White, ECOG performance score of 0 (56%) or 1 (44%), and 65% of patients had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies.

BAVENCIO was permanently discontinued for adverse reactions in six (7%) patients; adverse reactions resulting in permanent discontinuation were ileus, Grade 3 transaminitis, Grade 3 creatine kinase elevation, tubulointerstitial nephritis, and Grade 3 pericardial effusion. BAVENCIO was temporarily discontinued in 21 (24%) patients for adverse events, excluding temporary dose interruption for infusion-related reactions where infusion was restarted the same day. The most common adverse reaction requiring dose interruption was anemia. Serious adverse reactions that occurred in more than one patient were acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis. The most common adverse reactions (≥ 20%) were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.

Table 3 and Table 4 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, that occurred in patients receiving BAVENCIO.

Table 3: Adverse Reactions in ≥ 10% of Patients Receiving BAVENCIO in the JAVELIN Merkel 200 Trial
Adverse Reactions BAVENCIO(N=88)
All Grades% Grade 3-4%
*
Fatigue is a composite term that includes fatigue and asthenia.
Infusion-related reaction is a composite term that includes drug hypersensitivity, hypersensitivity, chills, pyrexia, back pain, and hypotension.
Peripheral edema is a composite term that includes peripheral edema and peripheral swelling.
§
Musculoskeletal pain is a composite term that includes back pain, myalgia, neck pain, pain in extremity.
Abdominal pain is a composite term that includes abdominal pain and abdominal pain upper.
#
Rash is a composite term that includes rash maculo-papular, erythema, and dermatitis bullous.
Þ
Pruritus is a composite term that includes pruritus and pruritus generalized.
ß
Dyspnea is a composite term that includes dyspnea and dyspnea exertional.
General Disorders
Fatigue * 50 2
Infusion-related reaction 22 0
Peripheral edema 20 0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain § 32 2
Arthralgia 16 1
Gastrointestinal Disorders
Diarrhea 23 0
Nausea 22 0
Constipation 17 1
Abdominal pain 16 2
Vomiting 13 0
Skin and Subcutaneous Tissue Disorders
Rash # 22 0
Pruritus Þ 10 0
Metabolism and Nutrition Disorders
Decreased appetite 20 2
Decreased weight 15 0
Respiratory, Thoracic and Mediastinal Disorders
Cough 18 0
Dyspnea ß 11 1
Nervous System Disorders
Dizziness 14 0
Headache 10 0
Vascular Disorders
Hypertension 13 6
Table 4: Selected Treatment-Emergent * Laboratory Abnormalities in Patients Receiving BAVENCIO in the JAVELIN Merkel 200 Trial
Laboratory Tests Any Grade(N=88)% Grade 3-4(N=88)%
*
Treatment emergent consists of new onset of laboratory abnormality or worsening of baseline laboratory abnormality.
Hyperglycemia limited to Grade ≥ 3 events since fasting measurements were not obtained routinely.
Chemistry
Increased aspartate aminotransferase (AST) 34 1
Increased alanine aminotransferase (ALT) 20 5
Increased lipase 14 4
Increased amylase 8 1
Increased bilirubin 6 1
Hyperglycemia 7
Hematology
Anemia 35 9
Lymphopenia 49 19
Thrombocytopenia 27 1
Neutropenia 6 1

Locally Advanced or Metastatic Urothelial Carcinoma

First-Line Maintenance Treatment of Urothelial Carcinoma

The safety of BAVENCIO was evaluated in the JAVELIN Bladder 100 trial where patients received BAVENCIO 10 mg/kg every 2 weeks plus best supportive care (BSC) (N=344) or BSC alone (N=345). Patients with autoimmune diseases or conditions requiring systemic immunosuppression were excluded.

In the BAVENCIO plus BSC arm, 47% were exposed to BAVENCIO for > 6 months and 28% were exposed for > 1 year [see Clinical Studies (14.2)].

The median age of patients treated with BAVENCIO plus BSC was 69 years (range: 37 to 90), 63% of patients were 65 years or older, 76% were male, 67% were White, and the ECOG performance score was 0 (61%) or 1 (39%).

A fatal adverse reaction (sepsis) occurred in one (0.3%) patient receiving BAVENCIO plus BSC.

Serious adverse reactions occurred in 28% of patients receiving BAVENCIO plus BSC. Serious adverse reactions in ≥ 1% of patients included urinary tract infection (including kidney infection, pyelonephritis, and urosepsis) (6.1%), pain (including abdominal, back, bone, flank, extremity, and pelvic pain) (3.2%), acute kidney injury (1.7%), hematuria (1.5%), sepsis (1.2%), and infusion-related reaction (1.2%).

Permanent discontinuation due to an adverse reaction of BAVENCIO plus BSC occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of BAVENCIO in > 1% of patients were myocardial infarction (including acute myocardial infarction and troponin T increased) (1.5%) and infusion-related reaction (1.2%).

Dose interruptions due to an adverse reaction, excluding temporary interruptions of BAVENCIO infusions due to infusion-related reactions, occurred in 41% of patients receiving BAVENCIO plus BSC. Adverse reactions leading to interruption of BAVENCIO in > 2% of patients were urinary tract infection (including pyelonephritis) (4.7%) and blood creatinine increased (including acute kidney injury, renal impairment, and renal failure) (3.8%).

The most common adverse reactions (≥ 20%) in patients receiving BAVENCIO plus BSC were fatigue, musculoskeletal pain, urinary tract infection, and rash.

Thirty-one (9%) patients treated with BAVENCIO plus BSC received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)].

Table 5 summarizes adverse reactions that occurred in ≥ 10% of patients treated with BAVENCIO plus BSC.

Table 5: Adverse Reactions (≥ 10%) of Patients Receiving BAVENCIO plus BSC (JAVELIN Bladder 100 Trial)
Adverse Reactions BAVENCIO plus BSC(N=344) BSC(N=345)
All Grades% Grade 3-4% All Grades% Grade 3-4%
*
Fatigue is a composite term that includes fatigue, asthenia and malaise.
Musculoskeletal pain is a composite term that includes musculoskeletal pain, back pain, myalgia, and neck pain.
Rash is a composite term that includes rash, rash maculo-papular, erythema, dermatitis acneiform, eczema, erythema multiforme, rash erythematous, rash macular, rash papular, rash pruritic, drug eruption and lichen planus.
§
Urinary tract infection is a composite term that includes urinary tract infection, urosepsis, cystitis, kidney infection, pyuria, pyelonephritis, bacteriuria, pyelonephritis acute, urinary tract infection bacterial, and Escherichia urinary tract infection.
Cough is a composite term that includes cough and productive cough.
General Disorders and Administration Site Conditions
Fatigue * 35 1.7 13 1.7
Pyrexia 15 0.3 3.5 0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain 24 1.2 15 2.6
Arthralgia 16 0.6 6 0
Skin and Subcutaneous Tissue Disorders
Rash 20 1.2 2.3 0
Pruritus 17 0.3 1.7 0
Infections and Infestations
Urinary tract infection § 20 6 11 3.8
Gastrointestinal Disorders
Diarrhea 17 0.6 4.9 0.3
Constipation 16 0.6 9.0 0
Nausea 16 0.3 6 0.6
Vomiting 13 1.2 3.5 0.6
Respiratory, Thoracic and Mediastinal Disorders
Cough 14 0.3 4.6 0
Metabolism and Nutrition Disorders
Decreased appetite 14 0.3 7 0.6
Endocrine disorders
Hypothyroidism 12 0.3 0.6 0
Injury, Poisoning and Procedural Complications
Infusion-related reaction 10 0.9 0 0

Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 10% (Grade 3: 0.9%) of patients treated with BAVENCIO plus BSC.

Table 6: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 10% of Patients Receiving BAVENCIO plus BSC (JAVELIN Bladder 100 Trial)
Laboratory Abnormality BAVENCIO plus BSC * BSC *
Any Grade% Grade 3-4% Any Grade% Grade 3-4%
*
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: BAVENCIO plus BSC group (range: 339 to 344 patients) and BSC group (range: 329 to 341 patients).
Chemistry
Blood triglycerides increased 34 2.1 28 1.2
Alkaline phosphatase increased 30 2.9 20 2.3
Blood sodium decreased 28 6 20 2.6
Lipase increased 25 8 16 6
Aspartate aminotransferase (AST) increased 24 1.7 12 0.9
Blood potassium increased 24 3.8 16 0.9
Alanine aminotransferase (ALT) increased 24 2.6 12 0.6
Blood cholesterol increased 22 1.2 16 0.3
Serum amylase increased 21 5 12 1.8
CPK increased 19 2.4 12 0
Phosphate decreased 19 3.2 15 1.2
Hematology
Hemoglobin decreased 28 4.4 18 3.2
White blood cell decreased 20 0.6 10 0
Platelet count decreased 18 0.6 12 0.3

Previously-Treated Urothelial Carcinoma

The safety of BAVENCIO was evaluated in 242 patients with locally advanced or metastatic UC receiving BAVENCIO at 10 mg/kg every 2 weeks in the UC cohorts of the JAVELIN Solid Tumor trial. Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. The median duration of exposure to BAVENCIO was 12 weeks (range: 2 weeks to 92 weeks) [see Clinical Studies (14.2)].

Fourteen patients (6%) who were treated with BAVENCIO experienced either pneumonitis, respiratory failure, sepsis/urosepsis, cerebrovascular accident, or gastrointestinal adverse events, which led to death.

Grade 1-4 serious adverse reactions were reported in 41% of patients. The most frequent serious adverse reactions reported in ≥ 2% of patients were urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestine obstruction, and pyrexia.

Permanent discontinuation due to an adverse reaction for BAVENCIO occurred in 12% of patients. The adverse reaction that resulted in permanent discontinuation in > 1% of patients was fatigue.

Dose interruptions due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 29% of patients receiving BAVENCIO. Adverse reactions leading to interruption of BAVENCIO in > 1% of patients were diarrhea, fatigue, dyspnea, urinary tract infection, and rash.

The most common Grade 3 and 4 adverse reactions (≥ 3%) were anemia, fatigue, hyponatremia, hypertension, urinary tract infection, and musculoskeletal pain.

The most common adverse reactions (≥ 20%) were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.

Eleven (4.5%) patients received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)].

Advanced Renal Cell Carcinoma

The safety of BAVENCIO was evaluated in JAVELIN Renal 101. Patients with autoimmune disease other than type I diabetes mellitus, vitiligo, psoriasis, or thyroid disorders not requiring immunosuppressive treatment were excluded. Patients received BAVENCIO 10 mg/kg every 2 weeks administered in combination with axitinib 5 mg twice daily (N=434) or sunitinib 50 mg once daily for 4 weeks followed by 2 weeks off (N=439).

In the BAVENCIO plus axitinib arm, 70% were exposed to BAVENCIO for ≥ 6 months and 29% were exposed for ≥ 1 year in JAVELIN Renal 101 [see Clinical Studies (14.3)].

The median age of patients treated with BAVENCIO in combination with axitinib was 62 years (range: 29 to 83), 38% of patients were 65 years or older, 71% were male, 75% were White, and the ECOG performance score was 0 (64%) or 1 (36%).

Fatal adverse reactions occurred in 1.8% of patients receiving BAVENCIO in combination with axitinib. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

Serious adverse reactions occurred in 35% of patients receiving BAVENCIO in combination with axitinib. Serious adverse reactions in ≥ 1% of patients included diarrhea (2.5%), dyspnea (1.8%), hepatotoxicity (1.8%), venous thromboembolic disease (1.6%), acute kidney injury (1.4%), and pneumonia (1.2%).

Permanent discontinuation due to an adverse reaction of either BAVENCIO or axitinib occurred in 22% of patients: 19% BAVENCIO only, 13% axitinib only, and 8% both drugs. The most common adverse reactions (> 1%) resulting in permanent discontinuation of BAVENCIO or the combination were hepatotoxicity (6%) and infusion-related reaction (1.8%).

Dose interruptions or reductions due to an adverse reaction, excluding temporary interruptions of BAVENCIO infusions due to infusion-related reactions, occurred in 76% of patients receiving BAVENCIO in combination with axitinib. This includes interruption of BAVENCIO in 50% of patients. Axitinib was interrupted in 66% and dose reduced in 19% of patients. The most common adverse reaction (> 10%) resulting in interruption of BAVENCIO was diarrhea (10%) and the most common adverse reactions resulting in either interruption or dose reduction of axitinib were diarrhea (19%), hypertension (18%), palmar-plantar erythrodysesthesia (18%), and hepatotoxicity (10%).

The most common adverse reactions (≥ 20%) in patients receiving BAVENCIO in combination with axitinib were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.

Forty-eight (11%) patients treated with BAVENCIO in combination with axitinib received an oral prednisone dose equivalent to ≥ 40 mg daily for an immune-mediated adverse reaction [see Warnings and Precautions (5)].

Table 7 summarizes adverse reactions that occurred in ≥ 20% of BAVENCIO in combination with axitinib-treated patients.

Table 7: Adverse Reactions (≥ 20%) of Patients Receiving BAVENCIO in Combination with Axitinib (JAVELIN Renal 101 Trial)
Adverse Reactions BAVENCIO plus Axitinib(N=434) Sunitinib(N=439)
All Grades% Grade 3-4% All Grades% Grade 3-4%
*
Diarrhea is a composite term that includes diarrhea, autoimmune colitis, and colitis.
Mucositis is a composite term that includes mucosal inflammation and stomatitis.
Hepatotoxicity is a composite term that includes ALT increased, AST increased, autoimmune hepatitis, bilirubin conjugated, bilirubin conjugated increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, hepatitis, hepatitis fulminant, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test increased, liver disorder, liver injury, and transaminases increased.
§
Abdominal pain is a composite term that includes abdominal pain, flank pain, abdominal pain upper, and abdominal pain lower.
Fatigue is a composite term that includes fatigue and asthenia.
#
Hypertension is a composite term that includes hypertension and hypertensive crisis.
Þ
Musculoskeletal pain is a composite term that includes musculoskeletal pain, musculoskeletal chest pain, myalgia, back pain, bone pain, musculoskeletal discomfort, neck pain, spinal pain, and pain in extremity.
ß
Rash is a composite term that includes rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, rash erythematous, rash papular, and rash pustular.
à
Dyspnea is a composite term that includes dyspnea, dyspnea exertional and dyspnea at rest.
Gastrointestinal Disorders
Diarrhea * 62 8 48 2.7
Nausea 34 1.4 39 1.6
Mucositis 34 2.8 35 2.1
Hepatotoxicity 24 9 18 3.6
Abdominal pain § 22 1.4 19 2.1
General Disorders and Administration Site Conditions
Fatigue 53 6 54 6
Vascular Disorders
Hypertension # 50 26 36 17
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain Þ 40 3.2 33 2.7
Skin and Subcutaneous Tissue Disorders
Palmar-plantar erythrodysesthesia 33 6 34 4
Rash ß 25 0.9 16 0.5
Respiratory, Thoracic and Mediastinal Disorders
Dysphonia 31 0.5 3.2 0
Dyspnea à 23 3 16 1.8
Cough 23 0.2 19 0
Metabolism and Nutrition Disorders
Decreased appetite 26 2.1 29 0.9
Endocrine Disorders
Hypothyroidism 25 0.2 14 0.2
Nervous System Disorders
Headache 21 0.2 16 0.2

Other clinically important adverse reactions that occurred in less than 20% of patients in JAVELIN Renal 101 included arthralgia, weight decreased, and chills.

Patients received pre-medication with an anti-histamine and acetaminophen prior to each infusion. Infusion-related reactions occurred in 12% (Grade 3: 1.6%; no Grade 4) of patients treated with BAVENCIO in combination with axitinib.

Table 8 summarizes selected laboratory abnormalities that occurred in ≥ 20% of BAVENCIO in combination with axitinib-treated patients.

Table 8: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20% of Patients Receiving BAVENCIO in Combination with Axitinib (JAVELIN Renal 101 Trial)
Laboratory Abnormality BAVENCIO plus Axitinib * Sunitinib *
Any Grade% Grade 3-4% Any Grade% Grade 3-4%
*
Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: BAVENCIO in combination with axitinib group (range: 413 to 428 patients) and sunitinib group (range: 405 to 433 patients).
Chemistry
Blood triglycerides increased 71 13 48 5
Blood creatinine increased 62 2.3 68 1.4
Blood cholesterol increased 57 1.9 22 0.7
Alanine aminotransferase increased (ALT) 50 9 46 3.2
Aspartate aminotransferase increased (AST) 47 7 57 3.2
Blood sodium decreased 38 9 37 10
Lipase increased 37 14 25 7
Blood potassium increased 35 3 28 3.9
Blood bilirubin increased 21 1.4 23 1.4
Hematology
Platelet count decreased 27 0.7 80 15
Hemoglobin decreased 21 2.1 65 8

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