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The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.
CODEINE SULFATE: EPIVIR-HBV (LAMIVUDINE)
- Added to warning September 2017
WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
EPIVIR-HBV is not approved for the treatment of HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment.
INVOKANA (CANAGLIFLOZIN)
- Added section to warning July 2017
WARNING: LOWER LIMB AMPUTATION
- An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
- Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
- Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.
INVOKAMET (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)
- Edited warning August 2017
WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
Lactic Acidosis
- Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Risk of Lower Limb Amputation
- In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.
INVOKAMET XR (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)
- Edited warning August 2017
WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
Lactic Acidosis
- Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/ pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. - Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
- Steps to reduce the risk of and manage metforminassociated lactic acidosis in these high risk groups are provided in the full prescribing information.
- If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Risk of Lower Limb Amputation
- An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
- Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
- Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
- Monitor patients receiving INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.
JEVTANA KIT (CABAZITAXEL)
- Edited warning September 2017
WARNING: NEUTROPENIA AND HYPERSENSITIVITY
Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.
THYRO-TABS (LEVOTHYROXINE SODIUM)
- Added section to warning August 2017
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
Thyroid hormones, including THYRO-TABS, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.
In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.
Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.
REGLAN (METOCLOPRAMIDE HYDROCHLORIDE)
- Edited warning August 2017
WARNING: TARDIVE DYSKINESIA
- Reglan can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage.
- Discontinue Reglan in patients who develop signs or symptoms of TD. In some patients, symptoms may lessen or resolve after Reglan is stopped.
- Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use.
The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.
CODEINE SULFATE: EPIVIR-HBV (LAMIVUDINE)
- Added to warning September 2017
WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
EPIVIR-HBV is not approved for the treatment of HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment.
INVOKANA (CANAGLIFLOZIN)
- Added section to warning July 2017
WARNING: LOWER LIMB AMPUTATION
- An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
- Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
- Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.
INVOKAMET (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)
- Edited warning August 2017
WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
Lactic Acidosis
- Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Risk of Lower Limb Amputation
- In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.
INVOKAMET XR (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)
- Edited warning August 2017
WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
Lactic Acidosis
- Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/ pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. - Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
- Steps to reduce the risk of and manage metforminassociated lactic acidosis in these high risk groups are provided in the full prescribing information.
- If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Risk of Lower Limb Amputation
- An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
- Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
- Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
- Monitor patients receiving INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.
JEVTANA KIT (CABAZITAXEL)
- Edited warning September 2017
WARNING: NEUTROPENIA AND HYPERSENSITIVITY
Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.
THYRO-TABS (LEVOTHYROXINE SODIUM)
- Added section to warning August 2017
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
Thyroid hormones, including THYRO-TABS, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.
In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.
Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.
REGLAN (METOCLOPRAMIDE HYDROCHLORIDE)
- Edited warning August 2017
WARNING: TARDIVE DYSKINESIA
- Reglan can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage.
- Discontinue Reglan in patients who develop signs or symptoms of TD. In some patients, symptoms may lessen or resolve after Reglan is stopped.
- Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use.
The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential benefit from the drug that it is essential that it be considered in assessing the risks and benefits of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.
CODEINE SULFATE: EPIVIR-HBV (LAMIVUDINE)
- Added to warning September 2017
WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, EXACERBATIONS OF HEPATITIS B, and RISK OF HIV-1 RESISTANCE IF EPIVIR-HBV IS USED IN PATIENTS WITH UNRECOGNIZED OR UNTREATED HIV-1 INFECTION
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPIVIR-HBV if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
EPIVIR-HBV is not approved for the treatment of HIV-1 infection because the lamivudine dosage in EPIVIR-HBV is subtherapeutic and monotherapy is inappropriate for the treatment of HIV-1 infection. HIV-1 resistance may emerge in chronic hepatitis B-infected patients with unrecognized or untreated HIV-1 infection. HIV counseling and testing should be offered to all patients before beginning treatment with EPIVIR-HBV and periodically during treatment.
INVOKANA (CANAGLIFLOZIN)
- Added section to warning July 2017
WARNING: LOWER LIMB AMPUTATION
- An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
- Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
- Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.
INVOKAMET (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)
- Edited warning August 2017
WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
Lactic Acidosis
- Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Risk of Lower Limb Amputation
- In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.
INVOKAMET XR (CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)
- Edited warning August 2017
WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
Lactic Acidosis
- Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/ pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. - Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
- Steps to reduce the risk of and manage metforminassociated lactic acidosis in these high risk groups are provided in the full prescribing information.
- If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Risk of Lower Limb Amputation
- An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
- Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
- Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
- Monitor patients receiving INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.
JEVTANA KIT (CABAZITAXEL)
- Edited warning September 2017
WARNING: NEUTROPENIA AND HYPERSENSITIVITY
Neutropenia: Neutropenic deaths have been reported. Monitor for neutropenia with frequent blood cell counts. JEVTANA is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.
THYRO-TABS (LEVOTHYROXINE SODIUM)
- Added section to warning August 2017
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS
Thyroid hormones, including THYRO-TABS, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss.
In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.
Larger doses may produce serious or even life threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.
REGLAN (METOCLOPRAMIDE HYDROCHLORIDE)
- Edited warning August 2017
WARNING: TARDIVE DYSKINESIA
- Reglan can cause tardive dyskinesia (TD), a serious movement disorder that is often irreversible. There is no known treatment for TD. The risk of developing TD increases with duration of treatment and total cumulative dosage.
- Discontinue Reglan in patients who develop signs or symptoms of TD. In some patients, symptoms may lessen or resolve after Reglan is stopped.
- Avoid treatment with Reglan for longer than 12 weeks because of the increased risk of developing TD with longer-term use.