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Drug Safety-related Labeling Changes (SrLC)

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CAMBIA (NDA-022165)

(DICLOFENAC POTASSIUM)

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

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11/21/2024 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Serious Skin Reactions

Additions and/or revisions underlined:

NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of CAMBIA at the first appearance of skin rash or any other sign of hypersensitivity.CAMBIA is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Adverse Reactions Reported With Diclofenac and Other NSAIDs

Other less frequently occurring adverse reactions identified during post approval use of diclofenac and other NSAIDs include fixed drug eruption [see Warnings and Precautions (5.9)].

04/28/2021 (SUPPL-13)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion; please refer to label)
8.2 Lactation

(PLLR conversion)

Risk Summary

Data from published literature reports with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk. There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMBIA and any potential adverse effects on the breastfed infant from CAMBIA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including CAMBIA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including CAMBIA, in women who have difficulties conceiving or who are undergoing investigation of infertility.

04/28/2021 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

(Newly added subsection)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as CAMBIA. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis.

Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue CAMBIA and evaluate the patient immediately.

5.12 Fetal Toxicity

(Subsection title revised; Additions and/or revisions underlined)

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including CAMBIA, in pregnant women at about 30 weeks gestation and later. NSAIDs, including CAMBIA, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including CAMBIA, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit CAMBIA use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if CAMBIA treatment extends beyond 48 hours. Discontinue CAMBIA if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Population (8.1)].

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.10)]

  • Medication Overuse Headache [see Warnings and Precautions (5.11)]

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

MEDICATION GUIDE

(Extensive changes to table; please refer to label)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Serious Skin Reactions, Including DRESS

Advise patients to stop taking CAMBIA immediately if they develop any type of rash, blisters, fever or other signs of hypersensitivity such as itching and to contact their healthcare provider as soon as possible. CAMBIA, like other NSAIDs, can cause serious skin reactions such as exfoliative dermatitis,

Steven-Johnson syndrome (SJS), toxic epidermal necrosis (TEN), and DRESS, which may result in hospitalizations and even death [see Warnings and Precautions (5.9, 5.10)].

Medication Overuse Headache

Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.11)].

Fetal Toxicity

Inform pregnant women to avoid use of CAMBIA and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with CAMBIA is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.12 and Use in Specific Populations (8.1)].

Lactation

Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in specific Populations (8.2)].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including CAMBIA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Use in Specific Populations (8.3)].

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of CAMBIA with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

Use of NSAIDS and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with CAMBIA until they talk to their healthcare provider [see Drug Interactions (7)].

03/20/2017 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Medication Overuse Headache

(Newly added subsection)

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, nonsteroidal anti-inflammatory drugs or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Medication Overuse Headache

Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary).

Medication Guide

(Additions and/or revisions are underlined)

What are the possible side effects of CAMBIA? CAMBIA can cause serious side effects, including:

See “What is the most important information I should know about CAMBIA?"

  • medication overuse headaches. Some people who use too much CAMBIA may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with CAMBIA.

05/09/2016 (SUPPL-11)

Approved Drug Label (PDF)

Boxed Warning

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

Cardiovascular Thrombotic Events
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
  • {Product} is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.
Gastrointestinal Bleeding, Ulceration, and Perforation
  • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

5 Warnings and Precautions

Cardiovascular Thrombotic Events

  • Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
  • To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
  • There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events.

     Status Post Coronary Artery Bypass Graft (CABG) Surgery

  • Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.

     Post-MI Patients

  • Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of {Product} in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If {Product} is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Heart Failure and Edema

  • The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
  • Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of {Product} may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).
  • Avoid the use of {Product} in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If {Product} is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

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

MG - Includes new safety information pertaining to the risks of Cardiovascular Thrombotic Events, Heart Failure and Edema.

 

PCI - Cardiovascular Thrombotic Events

  • Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately.

PCI - Heart Failure and Edema

  • Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.