Drug Safety-related Labeling Changes (SrLC)

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CYRAMZA (BLA-125477)

(RAMUCIRUMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/07/2025 (SUPPL-49)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of CYRAMZA in pediatric patients have not been established.

The safety and effectiveness of CYRAMZA were assessed but not established in a single-arm, multicenter, open-label trial [NCT02564198] that included 23 pediatric patients aged 1 year to  less than 17 years with relapsed or refractory solid tumors who received CYRAMZA as a single agent and two multicenter, randomized, controlled trials [NCT04145700 and NCT04145349] that included 16 pediatric patients aged 1 to less than 17 years with relapsed, recurrent, or progressive desmoplastic small round cell tumors or synovial sarcoma who received CYRAMZA in combination with chemotherapy versus chemotherapy alone. The effect on open tibial growth plates in pediatric patients who received CYRAMZA has not been adequately studied; however, one patient had progressive widening of distal femoral growth plate. No other new safety signals were observed in pediatric patients. The pharmacokinetic (PK) parameters for these pediatric patients who received CYRAMZA as a single agent or in combination was within the range of the values previously observed in adults given the same dose per body weight.

. . .

03/22/2022 (SUPPL-42)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

Newly added to bulleted line listing:

·       Cardiac: Heart failure

06/15/2021 (SUPPL-39)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of CYRAMZA in pediatric patients have not been established.

The safety and effectiveness of CYRAMZA as a single agent were assessed but not established in a single-arm, multicenter, open-label study [NCT02564198] that included 23 pediatric patients aged 1 year to 16 years with relapsed or refractory solid tumors. The effect on open tibial growth plates in pediatric patients who received CYRAMZA has not been adequately studied; however, one patient in this study had progressive widening of distal femoral growth plate. No other new safety signals were observed in pediatric patients. The pharmacokinetics (PK) for these pediatric patients was within the range of the values previously observed in adults given the same dose per body weight.

…

07/06/2020 (SUPPL-37)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

(Additions underlined)

…

• Vascular: Arterial (including aortic) aneurysms, dissections, and rupture

05/29/2020 (SUPPL-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined throughout all subsections:

5.1 Hemorrhage

CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade greater than or equal to3 hemorrhagic events. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence ranged from 2-5% [see Adverse Reactions (6.1)].

Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in REGARD and RAINBOW; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown.

Patients with NSCLC receiving therapeutic anticoagulation or with evidence of major airway invasion by cancer were excluded from REVEL. In addition, patients with NSCLC with a recent history of gross hemoptysis, those receiving chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin, or with radiographic evidence of major blood vessel invasion or intratumor cavitation were excluded from REVEL and RELAY; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown …

5.2 Gastrointestinal Perforations

CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2% [see Adverse Reactions (6.1)].

5.4 Arterial Thromboembolic Events

Serious, sometimes fatal, arterial thromboembolic events (ATEs), including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 1-3%. Grade 3-5 ATE incidence was <1-2% [see Adverse Reactions (6.1)].

5.5 Hypertension

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies, excluding RELAY, in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension ranged from 11-26%. Grade 3-5 hypertension incidence ranged from 6-15% [see Adverse Reactions (6.1)]. In 221 patients with NSCLC receiving CYRAMZA in combination with erlotinib in the RELAY study, the incidence of new or worsening hypertension was higher (45%), as was the incidence of Grade 3-5 hypertension (24%). Of the patients experiencing new or worsening hypertension in RELAY (N=100 CYRAMZA and erlotinib; N=27 placebo and erlotinib), 13% of those treated with CYRAMZA and erlotinib required initiation of 3 or more antihypertensive medications compared to 4% of patients treated with placebo and erlotinib.

Additions and/or revisions underlined throughout all subsections:

5.6 Infusion-Related Reactions

Infusion-related reactions (IRR), including severe and life-threatening IRR, occurred in CYRAMZA clinical trials … In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRR ranged from <1-9%. Grade 3-5 IRR incidence was <1% [see Adverse Reactions (6.1)] …

5.8 Posterior Reversible Encephalopathy Syndrome

Posterior Reversible Encephalopathy Syndrome (PRES) (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 2137 patients enrolled in six clinical studies with CYRAMZA …

5.9 Proteinuria including Nephrotic Syndrome

Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-34% …

5.10 Thyroid Dysfunction

Across six clinical studies in 2137 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism [see Adverse Reactions (6.1)]. Monitor thyroid function during treatment with CYRAMZA.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… The data described in the Warnings and Precautions section reflect exposure to CYRAMZA in 2137 patients from six studies: REGARD, RAINBOW, RAISE, REVEL, REACH-2, and RELAY …

Following Table 3: Adverse Reactions Occurring in greater than or equal to 5% of Patients with a less than or equal to 2% Difference Between Arms in RAINBOW: newly added information

Non-Small Cell Lung Cancer

CYRAMZA Administered in Combination with Erlotinib (RELAY)

The safety of CYRAMZA was evaluated in RELAY [see Clinical Studies (14.2)]. Patients had previously untreated EGFR exon 19 deletion or exon 21 (L858R) substitution mutation-positive metastatic NSCLC. Patients had ECOG PS 0 or 1.

RELAY excluded patients with bilirubin greater than the ULN, central nervous system (CNS) metastases, clinically active interstitial lung disease (ILD), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major blood vessel invasion or encasement by cancer or intra-tumor cavitation, or gross hemoptysis within the preceding 2 months. The study also excluded patients receiving chronic nonsteroidal anti-inflammatory agents (NSAIDs) or anti- platelet therapy other than once daily aspirin.

Patients received either CYRAMZA 10 mg/kg or placebo intravenously every two weeks in combination with erlotinib

150 mg taken orally once daily. Patients randomized to CYRAMZA received a median of 21 doses; the median duration of exposure was 11 months, and 90 (41% of 221) patients received CYRAMZA for at least 12 months.

The most common serious adverse reactions in patients who received CYRAMZA with erlotinib were pneumonia (3.2%), cellulitis (1.8%), and pneumothorax (1.8%). Red blood cell transfusions were given to 3.2% of CYRAMZA-treated patients versus 0 patients who received placebo.

Treatment discontinuation of all study drugs due to adverse reactions occurred in 13% of CYRAMZA with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of CYRAMZA were proteinuria (8.6%) and hyperbilirubinemia (6%).

The most common adverse reactions (all grades) observed in CYRAMZA with erlotinib-treated patients at a rate of greater than or equal to 30% of patients and greater than or equal to 2% higher than placebo with erlotinib-treated patients were infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities greater than or equal to 30% and greater than or equal to 2% higher than the placebo were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. Table 4 provides the frequency and severity of adverse reactions (CTCAE, version 4.0) and Table 5 provides the incidence and severity of laboratory abnormalities in RELAY.

The two below tables have been newly added to support the RELAY trial; please refer to label for completed information.

Table 4: Adverse Reactions Occurring in greater than or equal to 5% of Patients with a greater than or equal to 2% Difference Between Arms in RELAY

Table 5: Laboratory Abnormalities Worsening from Baseline in greater than or equal to 20% (All Grades) of Patients Receiving CYRAMZA with Erlotinib with a Difference Between Arms of greater than or equal to 2% in RELAY

CYRAMZA Administered in Combination with Docetaxel (REVEL)

The safety of CYRAMZA was evaluated in REVEL [see Clinical Studies (14.2)] …

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 563 CYRAMZA-treated patients in REGARD and RAINBOW, 205 (36%) were 65 and over, while 41 (7%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 221 patients who received CYZAMZA with erlotinib in RELAY, 119 (54%) were 65 and over, while 29 (13%) were 75 and over. Overall, no clinically meaningful differences in effectiveness were observed between these patients and younger patients. Adverse reactions occurring at a 10% or higher incidence in patients receiving CYRAMZA with erlotinib and with a 10% or greater difference between patients aged 65 or older compared to patients aged less than 65 years were: diarrhea (75% versus 65%), hypertension (50% versus 40%), increased ALT (49% versus 35%), increased AST (49% versus 33%), stomatitis (46% versus 36%), decreased appetite (32% versus 19%), dysgeusia (23% versus 12%), and weight loss (19% versus 6%).

Of the 1253 patients in REVEL, 455 (36%) were 65 and over and 84 (7%) were 75 and over …

02/20/2020 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Impaired Wound Healing

(subsection revised, additions underlined)

…

Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established.

6 Adverse Reactions

6.3 Postmarketing Experience

(additions underlined)

…

• Respiratory, thoracic, and mediastinal: Dysphonia

11/05/2019 (SUPPL-35)

5 Warnings and Precautions

5.8 Posterior Reversible Encephalopathy Syndrome

Additions and/or revisions underlined:

Posterior Reversible Encephalopathy Syndrome (PRES) (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 1916 patients enrolled in five clinical studies with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension.

Confirm the diagnosis of PRES with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death.

6 Adverse Reactions

Revision made to the bulleted line listing:

• ‘Posterior Reversible Encephalopathy Syndrome’ replaces ‘Reversible Posterior Leukoencephalopathy Syndrome’

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

Posterior Reversible Encephalopathy Syndrome

Advise patients to inform their health care provider if they develop neurological symptoms consistent with PRES (seizure, headache, nausea/vomiting, blindness, or altered consciousness).

07/31/2019 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Infusion-Related Reactions

(additions underlined)

Infusion-related reactions (IRR), including severe and life threatening IRR, occurred in CYRAMZA clinical trials.

…

Premedicate prior to each CYRAMZA infusion. Monitor patients during the infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Premedicate prior to each CYRAMZA infusion . Reduce the infusion rate by 50% for Grade 1-2 IRR. Permanently discontinue CYRAMZA for Grade 3-4 IRRs.

05/10/2019 (SUPPL-29)

5 Warnings and Precautions

5.1 Hemorrhage

(Additions and/or revisions are underlined)

CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including Grade greater than or equal to 3 hemorrhagic events. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hemorrhage occurred between 13-44%. Grade 3-5 hemorrhage incidence ranged from 2-5%.

Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in REGARD and RAINBOW; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown.

In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from REVEL; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown.

Permanently discontinue CYRAMZA in patients who experience severe (Grade 3 or 4) bleeding.

5.10 Thyroid Dysfunction

(Additions and/or revisions are underlined)

Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there were no reports of Grade 3-5 hypothyroidism. Monitor thyroid function during treatment with CYRAMZA.

5.2 Gastrointestinal Perforations

(Additions and/or revisions are underlined)

CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade and Grade 3-5 gastrointestinal perforations ranged from <1-2%.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

5.3 Impaired Wound Healing

(Additions and/or revisions are underlined)

Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF or VEGFR pathway. CYRAMZA, a VEGFR2 antagonist, has the potential to adversely affect wound healing. CYRAMZA has not been studied in patients with serious or non-healing wounds.

Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 28 days following a major surgical procedure and until the wound is fully healed. Discontinue CYRAMZA in patients who develop wound healing complications that require medical intervention.

5.4 Arterial Thromboembolic Events

(Additions and/or revisions are underlined)

Serious, sometimes fatal, arterial thromboembolic events (ATEs), including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia, occurred across clinical trials. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade ATE was 2-3%. Grade 3-5 ATE incidence was 1-2%.

Permanently discontinue CYRAMZA in patients who experience an ATE.

5.5 Hypertension

(Additions and/or revisions are underlined)

An increased incidence of severe hypertension occurred in patients receiving CYRAMZA. Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade hypertension occurred between 11-26%. Grade 3-5 hypertension incidence ranged from 6-15%.

Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Withhold CYRAMZA for severe hypertension until medically controlled.

Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

5.6 Infusion-Related Reactions

(Additions and/or revisions are underlined)

Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension.

Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA in which premedication was recommended or required, the incidence of all Grade IRRs occurred between <1-9%. Grade 3-5 IRRs incidence was <1%.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Premedicate prior to each CYRAMZA infusion. Reduce the infusion rate by 50% for Grade 1-2 IRRs. Permanently discontinue CYRAMZA for Grade 3-4 IRRs.

5.7 Worsening of Pre-existing Hepatic Impairment

(Additions and/or revisions are underlined)

Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single -agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Based on safety data from REACH-2, in patients with Child-Pugh A liver cirrhosis, the pooled incidence of hepatic encephalopathy and hepatorenal syndrome was higher for patients who received CYRAMZA (6%) compared to patients who received placebo (0%).

5.8 Reversible Posterior Leukoencephalopathy Syndrome

(Additions and/or revisions are underlined)

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in <0.1% of 1916 patients enrolled in five clinical studies with CYRAMZA.

Confirm the diagnosis of RPLS with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

5.9 Proteinuria Including Nephrotic Syndrome

(Additions and/or revisions are underlined)

Across five clinical studies in 1916 patients with various cancers treated with CYRAMZA, the incidence of all Grade proteinuria ranged from 3-20%. Grade greater than or equal to 3 proteinuria (including 4 patients with nephrotic syndrome) incidence ranged from <1-3%.

If the result of the urine dipstick is 2+ or greater, perform a 24-hour urine collection for protein measurement. Withhold CYRAMZA for urine protein levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA at a reduced dose once the urine protein level returns to less than 2 grams over 24 hours. Permanently discontinue CYRAMZA for urine protein levels greater than 3 grams over 24 hours or in the setting of nephrotic syndrome.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions are described elsewhere in the labeling:

• Worsening of Pre-existing Hepatic Impairment.

6.1 Clinical Trials Experience

(Extensive changes; please refer to labeling)

6.2 Immunogenicity

(Additions and/or revisions are underlined)

As with all therapeutic proteins, there is the potential for immunogenicity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

In clinical trials, 86/2890 (3%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients who tested positive for treatment-emergent anti-ramucirumab antibodies.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman. There are no available data on CYRAMZA use in pregnant women. Animal models link angiogenesis, VEGF and VEGFR2 to critical aspects of female reproduction, embryo-fetal development, and postnatal development. No animal studies have been conducted to evaluate the effect of ramucirumab on reproduction and fetal development. Advise a pregnant woman of the potential risk to a fetus.

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

There is no information on the presence of ramucirumab in human milk or its effects on the breastfed child or on milk production. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because of the potential risk for serious adverse reactions in breastfed children from ramucirumab, advise women not to breastfeed during treatment with CYRAMZA and for 2 months after the last dose.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating CYRAMZA.

Contraception

Based on its mechanism of action, CYRAMZA can cause fetal harm when administered to a pregnant woman.

Females

Advise females of reproductive potential to use effective contraception during treatment with CYRAMZA and for 3 months after the last dose.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness of CYRAMZA in pediatric patients have not been established.

Juvenile Animal Toxicity Data

In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology

revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5- 50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the 563 CYRAMZA-treated patients in REGARD and RAINBOW, 205 (36%) were 65 and over, while 41 (7%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 1253 patients in REVEL, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA with docetaxel in REVEL, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of REVEL, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years and over was 1.10 (95% CI: 0.89, 1.36).

Of the 529 patients who received CYRAMZA with FOLFIRI in RAISE, 209 (40%) were 65 and over, while 51 (10%) were 75 and over. Overall, no differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 197 patients who received CYRAMZA in REACH-2, 95 (48%) were 65 years and over, while 37 (19%) were 75 years and over. Overall, no differences in efficacy were observed between these subjects and younger subjects.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Gastrointestinal Perforations

Advise patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

Impaired Wound Healing

Advise patients that CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their healthcare provider.

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during CYRAMZA treatment and for 3 months after the last dose.

Lactation

Advise women not to breastfeed during CYRAMZA treatment and for 2 months after the last dose.

Infertility

Advise females of reproductive potential that CYRAMZA may impair fertility.

11/26/2018 (SUPPL-31)

6 Adverse Reactions

6.3 Postmarketing Experience

Additions and/or revisions underlined:

• Blood and lymphatic system: Thrombotic microangiopathy

• Neoplasms benign, malignant and unspecified: Hemangioma

08/14/2018 (SUPPL-30)

Approved Drug Label (PDF)

6 Adverse Reactions

6.3 Postmarketing Experience

(new subsection added)

The following adverse reaction has been identified during post-approval use of CYRAMZA. Because such reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Thrombotic microangiopathy