What the FDA changed in 2018

Approved uses

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Liraglutide has been studied in a limited number of patients with a history of pancreatitis.
• +Added: It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on Saxenda.
• +Added: Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists.

Removed in this revision

• -Removed: It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Saxenda, since these patients were excluded from clinical trials.
• -Removed: The clinical significance of the heart rate elevation with Saxenda treatment is unclear, especially for patients with cardiac and cerebrovascular disease as a result of limited exposure in these patients in clinical trials.
• -Removed: Angioedema has also been reported with other GLP-1 receptor agonists.

3 entries reworded without a change of meaning.

Adverse reactions

1 entry reworded without a change of meaning.

Dosage and administration

2 entries reworded without a change of meaning.

Forms and strengths

Added in this revision

• +Added: Each tablet contains doxycycline 120 mg (equivalent to doxycycline hyclate 138.8 mg).

Removed in this revision

• -Removed: Each tablet contains doxycycline 60 mg or 120 mg (equivalent to doxycycline hyclate 69.4 mg or 138.8 mg).

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Severe Skin Reactions Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline.
• +Added: If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.

Adverse reactions

Added in this revision

• +Added: Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported.
• +Added: Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development.

1 entry reworded without a change of meaning.

Dosage and administration

Removed in this revision

• -Removed: Dosage in Patients with Renal Impairment No dose adjustment is recommended in patients with renal impairment including end-stage renal disease (ESRD).
• -Removed: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions..

Forms and strengths

1 entry reworded without a change of meaning.

Warnings and precautions

1 entry reworded without a change of meaning.

Adverse reactions

Added in this revision

• +Added: Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis.

1 entry reworded without a change of meaning.

Approved uses

Added in this revision

• +Added: Treatment of Symptomatic Gastroesophageal Reflux Disease (GERD) PREVACID and PREVACID SoluTab are indicated for short-term treatment in adults and pediatric patients 12 to 17 years of age (up to eight weeks) and pediatric patients one to 11 years of age (up to 12 weeks) for the treatment of heartburn and other symptoms associated with GERD.

Removed in this revision

• -Removed: Treatment of Symptomatic Gastroesophageal Reflux Disease (GERD) PREVACID and PREVACID SoluTab are indicated in adults and pediatric patients one year of age and older for the treatment of heartburn and other symptoms associated with GERD for up to eight weeks.

Dosage and administration

Added in this revision

• +Added: Recommended Adult Dosage by Indication Recommended Pediatric Dosage by Indication Pediatric Patients 1 to 11 Years of Age In clinical studies, PREVACID was not administered beyond 12 weeks in 1 to 11 year olds.
• +Added: It is not known if PREVACID is safe and effective if used longer than the recommended duration.
• +Added: Do not exceed the recommended dose and duration of use in pediatric patients as outlined below.
• +Added: Pediatric Patients 12 to 17 Years of Age Hepatic Impairment The recommended dosage is 15 mg orally daily in patients with severe liver impairment (Child-Pugh C).

Removed in this revision

• -Removed: Recommended Adult Dosage by Indication Recommended Pediatric Dosage by Indication Hepatic Impairment The recommended dosage is 15 mg orally daily in patients with severe liver impairment (Child-Pugh C).

Warnings and precautions

Added in this revision

• +Added: Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year.
• +Added: Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy.
• +Added: Use the shortest duration of PPI therapy appropriate to the condition being treated.

Adverse reactions

1 entry reworded without a change of meaning.

Dosage and administration

Added in this revision

• +Added: No dose adjustment is required in patients with mild renal impairment.

Removed in this revision

• -Removed: There is a lack of adequate information to guide dosing in patients with mild renal impairment.

Adverse reactions

Added in this revision

• +Added: The observed increase in serum creatinine may be the result of OCT2 inhibition.

Removed in this revision

• -Removed: An in vitro drug-drug interaction study demonstrated that bupropion and its metabolites inhibit organic cation transporter 2 (OCT2), which is involved in the tubular secretion of creatinine, suggesting that the observed increase in serum creatinine may be the result of OCT2 inhibition.
• -Removed: Based on in vitro results and FDA guidance for Drug Interaction Studies, the ratios of the free (unbound) C max and IC50 value of bupropion and hydroxybupropion were well below 0.1 suggesting a drug-drug interaction between CONTRAVE and OCT2 substrate due to bupropion and hydroxybupropion is unlikely.
• -Removed: The ratio for the threohydrobupropion and erythrohydrobupropion metabolite mixture was 0.29, suggesting a drug-drug interaction between CONTRAVE and OCT2 due to threohydrobupropion and erythrohydrobupropion is possible.

Drug interactions

Removed in this revision

• -Removed: Drug-Transporter Interactions In vitro, CONTRAVE constituents inhibited the renal organic cation transporter OCT2 to a clinically relevant level.
• -Removed: The systemic concentrations of substrate drugs transported by OCT2 (such as amantadine, amiloride, cimetidine, dopamine, famotidine, memantine, metformin, pindolol, procainamide, ranitidine, varenicline, oxaliplatin) are likely to increase as a result of reduced renal clearance when coadministered with CONTRAVE.
• -Removed: Coadministration of CONTRAVE with such drugs should be approached with caution and patients should be monitored for adverse effects.

Warnings and precautions

Added in this revision

• +Added: Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year.
• +Added: Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy.
• +Added: Use the shortest duration of PPI therapy appropriate to the condition being treated.

Adverse reactions

2 entries reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year.
• +Added: Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy.
• +Added: Use the shortest duration of PPI therapy appropriate to the condition being treated.

Adverse reactions

Removed in this revision

• -Removed: 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.
• -Removed: During clinical trials, 2047 subjects with inflammatory lesions of rosacea received SOOLANTRA cream once daily.
• -Removed: A total of 1555 subjects were treated once daily for more than 12 weeks, and 519 for approximately one year.
• -Removed: Adverse reactions, reported in ≤ 1% of subjects treated with SOOLANTRA cream for at least 3 months in vehicle-controlled clinical trials, included skin burning sensation and skin irritation.
• -Removed: In postmarketing use with Soolantra, occurrences of contact dermatitis and allergic dermatitis have been reported.

Adverse reactions

Removed in this revision

• -Removed: Postmarketing Experience Additional adverse experiences have been reported since PREVACID and PREVACID SoluTab have been marketed.

Warnings and precautions

Added in this revision

• +Added: Elevation in Creatinine Qsymia can cause an increase in serum creatinine that reflects a decrease in renal function (glomerular filtration rate).
• +Added: In phase 3 trials, peak increases in serum creatinine were observed after 4 to 8 weeks of treatment.
• +Added: On average, serum creatinine gradually declined but remained elevated over baseline creatinine values.
• +Added: The changes in serum creatinine (and measured GFR) with short-term Qsymia treatment appear reversible with treatment discontinuation, but the effect of chronic treatment on renal function is not known.
• +Added: Therefore, measurement of serum creatinine prior to starting Qsymia and during Qsymia treatment is recommended.

Removed in this revision

• -Removed: Elevation in Creatinine Qsymia can cause an increase in serum creatinine.Peak increases in serum creatinine were observed after 4 to 8 weeks of treatment.
• -Removed: On average, serum creatinine gradually declined but remained elevated over baseline creatinine values Elevations in serum creatinine often signify a decrease in renal function, but the cause for Qsymia-associated changes in serum creatinine has not been definitively established..Therefore, measurement of serum creatinine prior to starting Qsymia and during Qsymia treatment is recommended.

Drug interactions

Removed in this revision

• -Removed: When topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

1 entry reworded without a change of meaning.

Approved uses

Added in this revision

• +Added: Heart Failure ALDACTONE is indicated for treatment of NYHA Class III-IV heart failure and reduced ejection fraction to increase survival, manage edema, and reduce the need for hospitalization for heart failure.
• +Added: ALDACTONE is usually administered in conjunction with other heart failure therapies.
• +Added: Hypertension ALDACTONE is indicated as add-on therapy for the treatment of hypertension, to lower blood pressure in patients who are not adequately controlled on other agents.
• +Added: Edema Associated with Hepatic Cirrhosis or Nephrotic Syndrome ALDACTONE is indicated for the management of edema in the following settings: Cirrhosis of the liver when edema is not responsive to fluid and sodium restriction.
• +Added: Because it increases serum potassium, ALDACTONE may be useful for treating edema when administration of other diuretics has caused hypokalemia.
• +Added: Primary Hyperaldosteronism ALDACTONE is indicated in the following settings: Short-term preoperative treatment of patients with primary hyperaldosteronism.
• +Added: Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are not candidates for surgery.

Removed in this revision

• -Removed: ALDACTONE (spironolactone) is indicated in the management of: Primary hyperaldosteronism for: Establishing the diagnosis of primary hyperaldosteronism by therapeutic trial.
• -Removed: Short-term preoperative treatment of patients with primary hyperaldosteronism.
• -Removed: Long-term maintenance therapy for patients with discrete aldosterone-producing adrenal adenomas who are judged to be poor operative risks or who decline surgery.
• -Removed: Edematous conditions for patients with: Congestive heart failure For the management of edema and sodium retention when the patient is only partially responsive to, or is intolerant of, other therapeutic measures.
• -Removed: ALDACTONE is also indicated for patients with congestive heart failure taking digitalis when other therapies are considered inappropriate.
• -Removed: Cirrhosis of the liver accompanied by edema and/or ascites Aldosterone levels may be exceptionally high in this condition.
• -Removed: ALDACTONE is indicated for maintenance therapy together with bed rest and the restriction of fluid and sodium.
• -Removed: Essential hypertension ALDACTONE is indicated for the treatment of hypertension, to lower blood pressure.
• -Removed: Usually in combination with other drugs, ALDACTONE is indicated for patients who cannot be treated adequately with other agents or for whom other agents are considered inappropriate.
• -Removed: Hypokalemia For the treatment of patients with hypokalemia when other measures are considered inappropriate or inadequate.
• -Removed: ALDACTONE is also indicated for the prophylaxis of hypokalemia in patients taking digitalis when other measures are considered inadequate or inappropriate.
• -Removed: Severe heart failure (NYHA class III - IV) To increase survival, and to reduce the need for hospitalization for heart failure when used in addition to standard therapy.

1 entry reworded without a change of meaning.

Dosage and administration

This section was substantially rewritten in this revision: 10 entries added, 18 removed. A change this large is usually a reorganization of the document rather than a set of individual edits, so the wording is not quoted line by line.

2 entries reworded without a change of meaning.

Forms and strengths

Added in this revision

• +Added: Tablets: 25 mg round, light yellow, film-coated, with SEARLE and 1001 debossed on one side and ALDACTONE and 25 on the other side.
• +Added: Tablets: 50 mg oval, light orange, scored, film-coated, with SEARLE and 1041 debossed on the scored side and ALDACTONE and 50 on the other side.
• +Added: Tablets: 100 mg round, peach-colored, scored, film-coated, with SEARLE and 1031 debossed on the scored side and ALDACTONE and 100 on the other side.

Contraindications

Added in this revision

• +Added: ALDACTONE is contraindicated in the patients with: Hyperkalemia Addison's disease Concomitant use of eplerenone

Removed in this revision

• -Removed: ALDACTONE is contraindicated for patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, hyperkalemia, Addison's disease, and with concomitant use of eplerenone.

Warnings and precautions

Added in this revision

• +Added: Hyperkalemia ALDACTONE can cause hyperkalemia.
• +Added: This risk is increased by impaired renal function or concomitant potassium supplementation, potassium-containing salt substitutes or drugs that increase potassium, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers.
• +Added: Monitor serum potassium within 1 week of initiation or titration of ALDACTONE and regularly thereafter.
• +Added: More frequent monitoring may be needed when ALDACTONE is given with other drugs that cause hyperkalemia or in patients with impaired renal function.
• +Added: If hyperkalemia occurs, decrease the dose or discontinue ALDACTONE and treat hyperkalemia.
• +Added: Hypotension and Worsening Renal Function Excessive diuresis may cause symptomatic dehydration, hypotension and worsening renal function, particularly in salt-depleted patients or those taking angiotensin converting enzyme inhibitors and angiotensin II receptor blockers.
• +Added: Worsening of renal function can also occur with concomitant use of nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs).
• +Added: Monitor volume status and renal function periodically.
• +Added: Electrolyte and Metabolic Abnormalities In addition to causing hyperkalemia, ALDACTONE can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, and hyperglycemia.
• +Added: Asymptomatic hyperuricemia can occur and rarely gout is precipitated.
• +Added: Monitor serum electrolytes, uric acid and blood glucose periodically.
• +Added: Gynecomastia ALDACTONE can cause gynecomastia.
• +Added: In RALES, patients with heart failure treated with a mean dose of 26 mg of spironolactone once daily, about 9% of the male subjects developed gynecomastia.
• +Added: The risk of gynecomastia increases in a dose-dependent manner with an onset that varies widely from 1-2 months to over a year.
• +Added: Gynecomastia is usually reversible.

Warnings

Removed in this revision

• -Removed: Potassium supplementation Potassium supplementation, either in the form of medication or as a diet rich in potassium, should not ordinarily be given in association with ALDACTONE therapy.
• -Removed: Excessive potassium intake may cause hyperkalemia in patients receiving ALDACTONE (see Precautions: General).
• -Removed: Concomitant administration of ALDACTONE with the following drugs or potassium sources may lead to severe hyperkalemia: other potassium-sparing diuretics ACE inhibitors angiotensin II antagonists aldosterone blockers non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin heparin and low molecular weight heparin other drugs or conditions known to cause hyperkalemia potassium supplements diet rich in potassium salt substitutes containing potassium ALDACTONE should not be administered...
• -Removed: ALDACTONE, when used with ACE inhibitors or indomethacin, even in the presence of a diuretic, has been associated with severe hyperkalemia.
• -Removed: Extreme caution should be exercised when ALDACTONE is given concomitantly with these drugs.
• -Removed: Hyperkalemia in patients with severe heart failure Hyperkalemia may be fatal.
• -Removed: It is critical to monitor and manage serum potassium in patients with severe heart failure receiving ALDACTONE.
• -Removed: Avoid using other potassium-sparing diuretics.
• -Removed: Avoid using oral potassium supplements in patients with serum potassium > 3.5 mEq/L.
• -Removed: RALES excluded patients with a serum creatinine > 2.5 mg/dL or a recent increase in serum creatinine > 25%.
• -Removed: The recommended monitoring for potassium and creatinine is one week after initiation or increase in dose of ALDACTONE, monthly for the first 3 months, then quarterly for a year, and then every 6 months.
• -Removed: Discontinue or interrupt treatment for serum potassium > 5 mEq/L or for serum creatinine > 4 mg/dL.
• -Removed: (See Clinical Studies: Severe heart failure, and Dosage and Administration: Severe heart failure.) ALDACTONE should be used with caution in patients with impaired hepatic function because minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
• -Removed: Lithium generally should not be given with diuretics (see Precautions: Drug interactions).

Adverse reactions

Added in this revision

• +Added: The following clinically significant adverse reactions are described elsewhere in the labeling: Hyperkalemia Hypotension and Worsening Renal Function Electrolyte and Metabolic Abnormalities Gynecomastia Impaired neurological function/ coma in patients with hepatic impairment, cirrhosis and ascites The following adverse reactions associated with the use of spironolactone were identified in clinical trials or postmarketing reports.
• +Added: Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency, reliably, or to establish a causal relationship to drug exposure.
• +Added: Reproductive: Decreased libido, inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast and nipple pain.
• +Added: Metabolism: Hyperkalemia, electrolyte disturbances, hyponatremia, hypovolemia.

Removed in this revision

• -Removed: The following adverse reactions have been reported and, within each category (body system), are listed in order of decreasing severity.
• -Removed: Reproductive: Gynecomastia (see Precautions), inability to achieve or maintain erection, irregular menses or amenorrhea, postmenopausal bleeding, breast pain.
• -Removed: Carcinoma of the breast has been reported in patients taking ALDACTONE but a cause and effect relationship has not been established.
• -Removed: Metabolism: Hyperkalemia, electrolyte disturbances (see Warnings and Precautions).

1 entry reworded without a change of meaning.

Drug interactions

This section was substantially rewritten in this revision: 10 entries added, 13 removed. A change this large is usually a reorganization of the document rather than a set of individual edits, so the wording is not quoted line by line.

2 entries reworded without a change of meaning.

Approved uses

1 entry reworded without a change of meaning.

Dosage and administration

Added in this revision

• +Added: Take a missed dose as soon as possible.
• +Added: If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time.
• +Added: Do not take 2 doses at the same time.

3 entries reworded without a change of meaning.

Contraindications

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Interference with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity.
• +Added: The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors.
• +Added: Healthcare providers should temporarily stop PROTONIX treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.
• +Added: If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.

1 entry reworded without a change of meaning.

Adverse reactions

3 entries reworded without a change of meaning.