What the FDA changed in 2022

Warnings and precautions

Added in this revision

• +Added: Oxalate Nephrolithiasis and Oxalate Nephropathy with Renal Failure Some patients may develop increased levels of urinary oxalate following treatment with XENICAL.
• +Added: Discontinue XENICAL in patients who develop oxalate nephropathy.

Removed in this revision

• -Removed: Increases in Urinary Oxalate Some patients may develop increased levels of urinary oxalate following treatment with XENICAL.

1 entry reworded without a change of meaning.

Approved uses

Added in this revision

• +Added: TRULICITY ® is indicated: As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus.

3 entries reworded without a change of meaning.

Dosage and administration

Added in this revision

• +Added: If additional glycemic control is needed, increase the dosage in 1.5 mg increments after at least 4 weeks on the current dosage.
• +Added: The maximum recommended dosage is 4.5 mg injected subcutaneously once weekly.
• +Added: Pediatric Dosage The recommended starting dosage of TRULICITY is 0.75 mg injected subcutaneously once weekly.
• +Added: If additional glycemic control is needed, increase the dosage to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75 mg dosage.
• +Added: Important Administration Instructions Prior to initiation, train patients and caregivers on proper injection technique.

Removed in this revision

• -Removed: If additional glycemic control is needed, increase the dose to 3 mg once weekly after at least 4 weeks on the 1.5 mg dose.
• -Removed: If additional glycemic control is needed, increase the dose to the maximum dose of 4.5 mg once weekly after at least 4 weeks on the 3 mg dose.

5 entries reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: TRULICITY is contraindicated in patients with a previous serious hypersensitivity reaction to dulaglutide or to any of the components of TRULICITY.

Removed in this revision

• -Removed: Do not use in patients with a previous hypersensitivity reaction to TRULICITY.

3 entries reworded without a change of meaning.

Adverse reactions

Added in this revision

• +Added: Sexual Function Questionnaire A sexual function questionnaire was self-administered by patients participating in the two vertex baldness trials to detect more subtle changes in sexual function.
• +Added: At Month 12, statistically significant differences in favor of placebo were found in 3 of 4 domains (sexual interest, erections, and perception of sexual problems).
• +Added: However, no significant difference was seen in the question on overall satisfaction with sex life.
• +Added: In one of the two vertex baldness studies, patients were questioned on non-scalp body hair growth.
• +Added: PROPECIA did not appear to affect non-scalp body hair.
• +Added: Nervous System/Psychiatric: depression, suicidal ideation and behavior.

Removed in this revision

• -Removed: Nervous System/Psychiatric: depression

Approved uses

Added in this revision

• +Added: Limitations of Use The effect of QSYMIA on cardiovascular morbidity and mortality has not been established.

2 entries reworded without a change of meaning.

Dosage and administration

This section was substantially rewritten in this revision: 20 entries added, 10 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.

4 entries reworded without a change of meaning.

Forms and strengths

1 entry reworded without a change of meaning.

Contraindications

Added in this revision

• +Added: QSYMIA is contraindicated in patients: Who are pregnant With glaucoma With hyperthyroidism Taking or within 14 days of stopping a monoamine oxidase inhibitors With known hypersensitivity to phentermine, topiramate or other component of QSYMIA, or idiosyncrasy to the sympathomimetic amines.

Removed in this revision

• -Removed: Qsymia is contraindicated in the following conditions: Pregnancy Glaucoma Hyperthyroidism During or within 14 days following the administration of monoamine oxidase inhibitors Known hypersensitivity or idiosyncrasy to the sympathomimetic amines.

Warnings and precautions

This section was substantially rewritten in this revision: 38 entries added, 32 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.

33 entries reworded without a change of meaning.

Adverse reactions

Added in this revision

• +Added: The following important adverse reactions are described elsewhere in the labeling: Embryo-Fetal Toxicity Increase in Heart Rate Suicidal Behavior and Ideation Risk of Ophthalmologic Adverse Reactions Mood and Sleep Disorders Cognitive Impairment Slowing of Linear Growth Metabolic Acidosis Decrease in Renal Function Risk of Seizures with Abrupt Withdrawal of QSYMIA Kidney Stones Oligohydrosis and Hyperthermia Hypokalemia Serious Skin Reactions

Removed in this revision

• -Removed: The following important adverse reactions are described below and elsewhere in the labeling: Fetal Toxicity: Elevation in Heart Rate Suicidal Behavior and Ideation Acute Angle Closure Glaucoma Mood and Sleep Disorders Cognitive Impairment Metabolic Acidosis 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 studies of another drug...
• -Removed: The data described herein reflects exposure to Qsymia in two, 1-year, randomized, double-blind, placebo-controlled, multicenter clinical trials, and two Phase 2 supportive trials in 2318 adult patients (936 [40.4%] patients with hypertension, 309 [13.3%] patients with type 2 diabetes, 808 [34.9%] patients with BMI greater than 40 kg/m 2) exposed for a mean duration of 298 days.
• -Removed: Common Adverse Reactions: Adverse reactions occurring at a rate of greater than or equal to 5% and at a rate at least 1.5 times placebo include paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.
• -Removed: Adverse reactions reported in greater than or equal to 2% of Qsymia-treated patients and more frequently than in the placebo group are shown in Table 3.
• -Removed: Paraesthesia/Dysgeusia Reports of paraesthesia, characterized as tingling in hands, feet, or face, occurred in 4.2%, 13.7%, and 19.9% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.9% of patients treated with placebo.
• -Removed: Dysgeusia was characterized as a metallic taste, and occurred in 1.3%, 7.4%, and 9.4% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 1.1% of patients treated with placebo.
• -Removed: The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatment.
• -Removed: Only Qsymia-treated patients discontinued treatment due to these events (1% for paraesthesia and 0.6% for dysgeusia).
• -Removed: Mood and Sleep Disorders The proportion of patients in 1-year controlled trials of Qsymia reporting one or more adverse reactions related to mood and sleep disorders was 15.8%, 14.5%, and 20.6% with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 10.3% with placebo.
• -Removed: These events were further categorized into sleep disorders, anxiety, and depression.
• -Removed: Reports of sleep disorders were typically characterized as insomnia, and occurred in 6.7%, 8.1%, and 11.1% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 5.8% of patients treated with placebo.
• -Removed: Reports of anxiety occurred in 4.6%, 4.8%, and 7.9% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 2.6% of patients treated with placebo.
• -Removed: Reports of depression/mood problems occurred in 5.0%, 3.8%, and 7.6% of patients treated with Qsymia 3.75 mg/23 mg, 7.5 mg/46 mg, and 15 mg/92 mg, respectively, compared to 3.4% of patients treated with placebo.
• -Removed: The majority of these events first occurred within the initial 12 weeks of drug therapy; however, in some patients, events were reported later in the course of treatments.
• -Removed: In the Qsymia clinical trials, the overall prevalence of mood and sleep adverse reactions was approximately twice as great in patients with a history of depression compared to patients without a history of depression; however, the proportion of patients on active treatment versus placebo who reported mood and sleep adverse reactions was similar in these two subgroups.
• -Removed: Occurrence of depression-related events was more frequent in patients with a past history of depression across all treatment groups.
• -Removed: However, the placebo-adjusted difference in incidence of these events remained constant between groups regardless of previous depression history.
• -Removed: Cognitive Disorders In the 1-year controlled trials of Qsymia, the proportion of patients who experienced one or more cognitive-related adverse reactions was 2.1% for Qsymia 3.75 mg/23 mg, 5.0% for Qsymia 7.5 mg/46 mg, and 7.6% for Qsymia 15 mg/92 mg, compared to 1.5% for placebo.
• -Removed: These adverse reactions were comprised primarily of reports of problems with attention/concentration, memory, and language (word finding).
• -Removed: These events typically began within the first 4 weeks of treatment, had a median duration of approximately 28 days or less, and were reversible upon discontinuation of treatment; however, individual patients did experience events later in treatment, and events of longer duration.
• -Removed: Laboratory Abnormalities Serum Bicarbonate In the 1-year controlled trials of Qsymia, the incidence of persistent treatment-emergent decreases in serum bicarbonate below the normal range (levels of less than 21 mEq/L at 2 consecutive visits or at the final visit) was 8.8% for Qsymia 3.75 mg/23 mg, 6.4% for Qsymia 7.5 mg/46 mg, and 12.8% for Qsymia 15 mg/92 mg, compared to 2.1% for placebo.
• -Removed: The incidence of persistent, markedly low serum bicarbonate values (levels of less than 17 mEq/L on 2 consecutive visits or at the final visit) was 1.3% for Qsymia 3.75 mg/23 mg, 0.2% for Qsymia 7.5 mg/46 mg dose, and 0.7% for Qsymia 15 mg/92 mg dose, compared to 0.1% for placebo.
• -Removed: Generally, decreases in serum bicarbonate levels were mild (average 1-3 mEq/L) and occurred early in treatment (4-week visit), however severe decreases and decreases later in treatment occurred.
• -Removed: Serum Potassium In the 1-year controlled trials of Qsymia, the incidence of persistent low serum potassium values (less than 3.5 mEq/L at two consecutive visits or at the final visit) during the trial was 0.4% for Qsymia 3.75 mg/23 mg, 3.6% for Qsymia 7.5 mg/46 mg dose, and 4.9% for Qsymia 15 mg/92 mg, compared to 1.1% for placebo.
• -Removed: Of the subjects who experienced persistent low serum potassium, 88% were receiving treatment with a non-potassium sparing diuretic.
• -Removed: The incidence of markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L) at any time during the trial was 0.0% for Qsymia 3.75 mg/23 mg, 0.2% for Qsymia 7.5 mg/46 mg dose, and 0.7% for Qsymia 15 mg/92 mg dose, compared to 0.0% for placebo.
• -Removed: Persistent markedly low serum potassium (less than 3 mEq/L, and a reduction from pre-treatment of greater than 0.5 mEq/L at two consecutive visits or at the final visit) occurred in 0.0% of subjects receiving Qsymia 3.75 mg/23 mg, 0.2% receiving Qsymia 7.5 mg/46 mg dose, and 0.1% receiving Qsymia 15 mg/92 mg dose, compared to 0.0% receiving placebo.
• -Removed: Hypokalemia was reported by 0.4% of subjects treated with Qsymia 3.75 mg/23 mg, 1.4% of subjects treated with Qsymia 7.5 mg/46 mg, and 2.5% of subjects treated with Qsymia 15 mg/92 mg compared to 0.4% of subjects treated with placebo. "Blood potassium decreased" was reported by 0.4% of subjects treated with Qsymia 3.75 mg/23 mg, 0.4% of subjects treated with Qsymia 7.5 mg/46 mg, 1.0% of subjects treated with Qsymia 15 mg/92 mg, and 0.0% of subjects treated with placebo.
• -Removed: Serum Creatinine In the 1-year controlled trials of Qsymia, there was a dose-related increase from baseline, peaking between Week 4 to 8, which declined but remained elevated over baseline over 1 year of treatment.
• -Removed: The incidence of increases in serum creatinine of greater than or equal to 0.3 mg/dL at any time during treatment was 2.1% for Qsymia 3.75 mg/23 mg, 7.2% for Qsymia 7.5 mg/46 mg, and 8.4% for Qsymia 15 mg/92 mg, compared to 2.0% for placebo.
• -Removed: Increases in serum creatinine of greater than or equal to 50% over baseline occurred in 0.8% of subjects receiving Qsymia 3.75 mg/23 mg, 2.0% receiving Qsymia 7.5 mg/46 mg, and 2.8% receiving Qsymia 15 mg/92 mg, compared to 0.6% receiving placebo.
• -Removed: Nephrolithiasis In the 1-year controlled trials of Qsymia, the incidence of nephrolithiasis was 0.4% for Qsymia 3.75 mg/23 mg, 0.2% for Qsymia 7.5 mg/46 mg, and 1.2% for Qsymia 15 mg/92 mg, compared to 0.3% for placebo.
• -Removed: Drug Discontinuation Due to Adverse Reactions In the 1-year placebo-controlled clinical studies, 11.6% of Qsymia 3.75 mg/23 mg, 11.6% of Qsymia 7.5 mg/46 mg, 17.4% of Qsymia 15 mg/92 mg, and 8.4% of placebo-treated patients discontinued treatment due to reported adverse reactions.
• -Removed: The most common adverse reactions that led to discontinuation of treatment are shown in Table 4.
• -Removed: Postmarketing Experience The following adverse reactions have been reported during post approval use of phentermine and topiramate, the components of Qsymia.
• -Removed: Because these 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.
• -Removed: Qsymia Psychiatric Disorders Suicidal ideation, Suicidal behavior Ophthalmic disorders Acute angle closure glaucoma Increased intraocular pressure Phentermine Allergic adverse reactions Urticaria Cardiovascular adverse reactions Elevation of blood pressure, Ischemic events Central nervous system adverse reactions Euphoria, Psychosis, Tremor Reproductive adverse reactions Changes in libido, Impotence Topiramate Dermatologic disorders Bullous skin reactions (including erythema multiforme,...

Drug interactions

Added in this revision

• +Added: Table 7 displays clinically significant drug interactions with QSYMIA.

Removed in this revision

• -Removed: Drug Interactions In Vitro Assessment of Drug Interactions Phentermine Phentermine is not an inhibitor of CYP isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, and is not an inhibitor of monoamine oxidases.
• -Removed: Phentermine is not an inducer of CYP1A2, CYP2B6, and CYP3A4.
• -Removed: Phentermine is not a P-glycoprotein substrate.
• -Removed: Topiramate Topiramate is not an inhibitor of CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4/5.
• -Removed: However, topiramate is a mild inhibitor of CYP2C19.
• -Removed: Topiramate is a mild inducer of CYP3A4.
• -Removed: Topiramate is not a P-glycoprotein substrate.
• -Removed: Effects of Phentermine/Topiramate on Other Drugs Effect of Other Drugs on Phentermine/Topiramate Effects of Topiramate Alone on Other Drugs and Effects of Other Drugs on Topiramate Antiepileptic Drugs Potential interactions between topiramate and standard antiepileptic (AED) drugs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy.
• -Removed: The effects of these interactions on mean plasma AUCs are summarized in Table 7.
• -Removed: In Table 7, the second column (AED concentration) describes what happens to the concentration of the AED listed in the first column when topiramate is added.
• -Removed: The third column (topiramate concentration) describes how the co-administration of a drug listed in the first column modifies the concentration of topiramate in experimental settings when topiramate was given alone.
• -Removed: Digoxin In a single-dose study, serum digoxin AUC was decreased by 12% with concomitant topiramate administration.
• -Removed: The clinical relevance of this observation has not been established.
• -Removed: Hydrochlorothiazide A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of hydrochlorothiazide (HCTZ) (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly.
• -Removed: The results of this study indicate that topiramate C max increased by 27% and AUC increased by 29% when HCTZ was added to topiramate.
• -Removed: The clinical significance of this change is unknown.
• -Removed: The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate.
• -Removed: Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.
• -Removed: Pioglitazone A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate (96 mg twice daily) and pioglitazone (30 mg daily) when administered alone and concomitantly for 7 days.
• -Removed: A 15% decrease in the area under the concentration-time curve during a dosage interval at steady state (AUC τ,ss) of pioglitazone with no alteration in maximum steady-state plasma drug concentration during a dosage interval (C max,ss) was observed.
• -Removed: This finding was not statistically significant.
• -Removed: In addition, a 13% and 16% decrease in C max,ss and AUC τ,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in C max,ss and AUC τ,ss of the active keto-metabolite.
• -Removed: The clinical significance of these findings is not known.
• -Removed: Glyburide A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day).
• -Removed: There was a 22% decrease in C max and a 25% reduction in AUC 24 for glyburide during topiramate administration.
• -Removed: Systemic exposure (AUC) of the active metabolites, 4- trans -hydroxyglyburide (M1), and 3- cis -hydroxyglyburide (M2), was reduced by 13% and 15%, and C max was reduced by 18% and 25%, respectively.
• -Removed: The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.
• -Removed: Lithium In patients, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for C max and 26% for AUC) following topiramate doses up to 600 mg/day.
• -Removed: Lithium levels should be monitored when co-administered with high-dose topiramate.
• -Removed: Haloperidol The pharmacokinetics of a single dose of haloperidol (5 mg) were not affected following multiple dosing of topiramate (100 mg every 12 hours) in 13 healthy adults (6 males, 7 females).
• -Removed: Amitriptyline There was a 12% increase in AUC and C max for amitriptyline (25 mg per day) in 18 normal subjects (9 males, 9 females) receiving 200 mg/day of topiramate.
• -Removed: Some subjects may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.
• -Removed: Sumatriptan Multiple dosing of topiramate (100 mg every 12 hrs) in 24 healthy volunteers (14 males, 10 females) did not affect the pharmacokinetics of single-dose sumatriptan either orally (100 mg) or subcutaneously (6 mg).
• -Removed: Risperidone When administered concomitantly with topiramate at escalating doses of 100, 250, and 400 mg/day, there was a reduction in risperidone systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses of topiramate).
• -Removed: No alterations of 9-hydroxyrisperidone levels were observed.
• -Removed: Co-administration of topiramate 400 mg/day with risperidone resulted in a 14% increase in C max and a 12% increase in AUC 12 of topiramate.
• -Removed: There were no clinically significant changes in the systemic exposure of risperidone plus 9-hydroxyrisperidone or of topiramate; therefore, this interaction is not likely to be of clinical significance.
• -Removed: Propranolol Multiple dosing of topiramate (200 mg/day) in 34 healthy volunteers (17 males, 17 females) did not affect the pharmacokinetics of propranolol following daily 160 mg doses.
• -Removed: Propranolol doses of 160 mg/day in 39 volunteers (27 males, 12 females) had no effect on the exposure to topiramate, at a dose of 200 mg/day of topiramate.
• -Removed: Dihydroergotamine Multiple dosing of topiramate (200 mg/day) in 24 healthy volunteers (12 males, 12 females) did not affect the pharmacokinetics of a 1 mg subcutaneous dose of dihydroergotamine.
• -Removed: Similarly, a 1 mg subcutaneous dose of dihydroergotamine did not affect the pharmacokinetics of a 200 mg/day dose of topiramate in the same study.
• -Removed: Diltiazem Co-administration of diltiazem (240 mg Cardizem CD ®) with topiramate (150 mg/day) resulted in a 10% decrease in C max and a 25% decrease in diltiazem AUC, a 27% decrease in C max and an 18% decrease in des-acetyl diltiazem AUC, and no effect on N-desmethyl diltiazem.
• -Removed: Co-administration of topiramate with diltiazem resulted in a 16% increase in C max and a 19% increase in AUC 12 of topiramate.
• -Removed: Venlafaxine Multiple dosing of topiramate (150 mg/day) in healthy volunteers did not affect the pharmacokinetics of venlafaxine or O-desmethyl venlafaxine.
• -Removed: Multiple dosing of venlafaxine (150 mg extended release) did not affect the pharmacokinetics of topiramate.

Dosage and administration

1 entry reworded without a change of meaning.

Contraindications

Added in this revision

• +Added: Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with SAXENDA. • Pregnancy.

1 entry reworded without a change of meaning.

Warnings and precautions

1 entry reworded without a change of meaning.

Dosage and administration

Added in this revision

• +Added: No dose adjustment is needed if changing the injection site and/or timing. • Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis. • When using VICTOZA with insulin, administer as separate injections.

Removed in this revision

• -Removed: No dose adjustment is needed if changing the injection site and/or timing. • When using VICTOZA with insulin, administer as separate injections.

1 entry reworded without a change of meaning.

Contraindications

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing.

Removed in this revision

• -Removed: The majority of events required hospitalization or cholecystectomy.

1 entry reworded without a change of meaning.

Adverse reactions

Added in this revision

• +Added: The majority of events required hospitalization or cholecystectomy.

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing.
• +Added: In placebo-controlled trials, cholelithiasis was reported in 1% of patients treated with RYBELSUS 7 mg.
• +Added: Cholelithiasis was not reported in RYBELSUS 14 mg or placebo-treated patients.
• +Added: If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

Adverse reactions

Added in this revision

• +Added: Hypersensitivity: anaphylaxis, angioedema, rash, urticaria Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy

Removed in this revision

• -Removed: Hypersensitivity: anaphylaxis, angioedema, rash, urticaria

1 entry reworded without a change of meaning.

Contraindications

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing.
• +Added: In a cardiovascular outcomes trial with a median follow up of 5.4 years, cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy.
• +Added: Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively.
• +Added: If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

Adverse reactions

1 entry reworded without a change of meaning.

Dosage and administration

1 entry reworded without a change of meaning.

Warnings

Added in this revision

• +Added: Symptoms include: • skin reddening • blisters • rash If an allergic reaction occurs, stop use and seek medical attention right away.

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs.
• +Added: Discontinue PROTONIX at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
• +Added: Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients.
• +Added: Consider monitoring magnesium and calcium levels prior to initiation of PROTONIX and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism).
• +Added: Supplement with magnesium and/or calcium as necessary.
• +Added: If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

Removed in this revision

• -Removed: Serological testing (e.g.

2 entries reworded without a change of meaning.

Adverse reactions

1 entry reworded without a change of meaning.

Approved uses

Removed in this revision

• -Removed: Efficacy of ORACEA beyond 16 weeks and safety beyond 9 months have not been established.

1 entry reworded without a change of meaning.

Dosage and administration

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Inhibition of Bone Growth During Fetal and Pediatric Development Doxycycline, like other tetracycline-class drugs, may cause inhibition of bone growth when administered during the second and third trimesters of pregnancy, infancy, and childhood.
• +Added: If doxycycline is used during the second or third trimester of pregnancy, advise the patient of the potential risk to the fetus.
• +Added: Use of tetracycline drugs is not recommended during tooth development.
• +Added: Appropriate management should be instituted as clinically indicated.

Removed in this revision

• -Removed: Teratogenic Effects ORACEA should not be used during pregnancy.
• -Removed: Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm when administered to a pregnant woman.
• -Removed: If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be informed of the potential hazard to the fetus and treatment stopped immediately.
• -Removed: Tetracycline drugs, therefore, should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.
• -Removed: Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can cause retardation of skeletal development on the developing fetus.
• -Removed: Evidence of embryotoxicity has been noted in animals treated early in pregnancy.
• -Removed: Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

2 entries reworded without a change of meaning.

Drug interactions

Removed in this revision

• -Removed: Low Dose Oral Contraceptives Doxycycline may interfere with the effectiveness of low dose oral contraceptives.
• -Removed: To avoid contraceptive failure, females are advised to use a second form of contraceptive during treatment with doxycycline.

Warnings and precautions

Added in this revision

• +Added: Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs.
• +Added: Discontinue PREVACID or PREVACID SoluTab at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
• +Added: Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients.
• +Added: Consider monitoring magnesium and calcium levels prior to initiation of PREVACID or PREVACID SoluTab and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism).
• +Added: Supplement with magnesium and/or calcium, as necessary.
• +Added: If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

2 entries reworded without a change of meaning.

Adverse reactions

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs.
• +Added: Discontinue NEXIUM at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
• +Added: Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients.
• +Added: Consider monitoring magnesium and calcium levels prior to initiation of NEXIUM and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism).
• +Added: Supplement with magnesium and/or calcium, as necessary.
• +Added: If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

1 entry reworded without a change of meaning.

Adverse reactions

Added in this revision

• +Added: Metabolism and nutritional disorders: hypomagnesemia (may lead to hypocalcemia and/or hypokalemia);
• +Added: Skin and Subcutaneous Tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), cutaneous lupus erythematosus.

Removed in this revision

• -Removed: Metabolism and nutritional disorders: hypomagnesemia, with or without hypocalcemia and/or hypokalemia;
• -Removed: Skin and Subcutaneous Tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), cutaneous lupus erythematosus.

2 entries reworded without a change of meaning.