Drug Safety-related Labeling Changes (SrLC)

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PREVPAC (NDA-050757)

(AMOXICILLIN; CLARITHROMYCIN; LANSOPRAZOLE)

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

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06/07/2018 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

Pediatric Use

Newly added information:

Juvenile Animal Toxicity Data

In a juvenile rat study, adverse effects on bone growth and development and heart valves were observed at lansoprazole doses higher than the maximum recommended equivalent human dose.

An eight-week oral toxicity study with a four-week recovery phase was conducted in juvenile rats, with lansoprazole administered from postnatal Day 7 (age equivalent to neonatal humans) through 62 (age equivalent to approximately 14 years in humans) at doses of 40 to 500 mg/kg/day (about 1.2 to 12 times the daily pediatric dose of 15 mg in children age one to 11 years weighing 30 kg or less, based on AUC).

Heart valve thickening occurred at a dose of 500 mg/kg/day (approximately 12 times the daily dose of 15 mg in pediatric patients age one to 11 years weighing 30 kg or less, based on AUC). Heart valve thickening was not observed at the next lower dose (250 mg/kg/day) and below. The findings trended towards reversibility after a four-week drug-free recovery period. The relevance of heart valve thickening in this study to pediatric patients less than approximately 12 years of age is unknown. These findings are not relevant for patients 12 years of age and older. No effects on heart valves were observed in a 13-week intravenous toxicity study of lansoprazole in adolescent rats (approximately 12 years human age equivalence) at systemic exposures similar to those achieved in the eight-week oral toxicity study in juvenile (neonatal) rats.

In the eight-week oral toxicity study, doses equal to or greater than 100 mg/kg/day (about 2.5 times the daily pediatric dose of 15 mg in children age one to 11 years weighing 30 kg or less, based on AUC) produced delayed growth, with impairment of weight gain observed as early as postnatal Day 10 (age equivalent to neonatal humans). At the end of treatment, the signs of impaired growth at 100 mg/kg/day and higher included reductions in body weight (14% to 44% compared to controls), absolute weight of multiple organs, femur weight, femur length, and crown-rump length. Femoral growth plate thickness was reduced only in males and only at the 500 mg/kg/day dose. The effects related to delayed growth persisted through the end of the 4- week recovery period. Longer term data were not collected.

PRECAUTIONS

Pregnancy

Lansoprazole

Additions and/or revisions underlined:

No adverse effects on embryo-fetal development occurred in studies performed in pregnant rats at oral lansoprazole doses up to 150 mg/kg/day (40 times the recommended human dose [30

mg/day] based on body surface area) administered during organogenesis and pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day (16 times the recommended human dose based

on body surface area) administered during organogenesis.

Newly added information:

A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with lansoprazole at oral doses of 10 to 100 mg/kg/day (0.7 to 6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC [area under the plasma concentration-time curve]) administered during organogenesis through lactation. Maternal effects observed at 100 mg/kg/day (6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC) included increased gestation period, decreased body weight gain during gestation, and decreased food consumption. The number of stillbirths was increased at this dose, which may have been secondary to maternal toxicity. Body weight of pups was reduced at 100 mg/kg/day starting on postnatal Day 11. Femur weight, femur length, and crown-rump length were reduced at 100 mg/kg/day on postnatal Day 21. Femur weight was still decreased in the 100 mg/kg/day group at age 17 to 18 weeks. Growth plate thickness was decreased in the 100 mg/kg/day males on postnatal Day 21, and was increased in the 30 and 100 mg/kg/day males at age 17 to 18 weeks. The effects on bone parameters were associated with reduction in body weight gain.

11/29/2017 (SUPPL-21)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

…Proton Pump Inhibitors (PPIs), including PREVACID, are contraindicated with rilpivirine-containing products.

5 Warnings and Precautions

WARNINGS

(Additions and/or revisions are underlined)

…

Interactions with Investigations for Neuroendocrine Tumors

Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop lansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. 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.

Interaction with Methotrexate

…In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients.

7 Drug Interactions

(Additions and/or revisions are underlined)

…

Tables 5 and 6 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PREVACID and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

Table 5. Clinically Relevant Interactions Affecting Drugs Coadministered with PREVACID and Interactions with Diagnostics (Table has been added; please refer to label)

Table 6. Clinically Relevant Interactions Affecting PREVACID When Coadministered with Other Drugs (Table has been added; please refer to label)

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

Information for Patients

 (Additions and/or revisions are underlined)

…

Advise patients to report to their healthcare provider if they are taking rilpivirine-containing products or high-dose methotrexate.

03/01/2017 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

General

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfections occur, PREVPAC should be discontinued and appropriate therapy instituted.

Prescribing PREVPAC either in the absence of a proven or strongly suspected bacterial infection …

Drug Interactions

PREVACID

… As with other drugs that decrease the intragastric acidity, the absorption of drugs such as ampicillin esters, ketoconazole, atazanavir, nelfinavir, iron salts …

Atazanavir and Nelfinavir: PREVACID substantially decreases the systemic concentrations of HIV protease  inhibitors, such as atazanavir and nelfinavir, which are dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir or nelfinavir and the development of HIV resistance. Therefore, PREVACID should not be co-administered with atazanavir or nelfinavir.

Drugs Metabolized by P450 Enzymes: PREVACID is metabolized through the cytochrome P450 system (CYP450), specifically  through the CYP3A and CYP2C19 isozymes. Studies in healthy subjects have shown that PREVACID does not have clinically significant interactions with other drugs metabolized by CYP450,  such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds …

Following the Amoxicilln section in Drug Interaction, is a newly added table entiltled Table 5: Clinically Significant Drug Interactions with BIAXIN; please refer to label.

Drug/Laboratory Test Interactions

… Following administration of ampicillin or amoxicillin to pregnant women …

Nursing Mothers

… Clarithromycin and its active metabolite 14-hydroxy clarithromycin are excreted in human milk. Serum and milk samples were obtained after three days of treatment, at steady state, from one published study of 12 lactating women who were taking clarithromycin 250 mg orally twice daily. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk-fed infant would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with this maternal dosage regimen. This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than six months of age.

A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibiotic (six were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence.

Caution should be exercised when clarithromycin is administered to nursing women. The development and health benefits of human milk feeding should be considered along with the mother’s clinical need for clarithromycin and any potential adverse effects on the human milk- fed child from the drug  or from the underlying maternal condition.

Geriatric Use

An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged  and over respond differently from younger subjects.  These analyses have not identified differences …

… Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients ...

Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older.

WARNINGS

Hepatotoxicity

Additions and/or revisions underlined:

… This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue clarithromycin immediately …

Drug Interactions

Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia with disopyramide, and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older. Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme.

Benzodiazepines

Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam.

6 Adverse Reactions

PREVPAC

Table 5 6. Adverse Reactions Most Frequently Reported in Clinical Trials (?3%)

Amoxicillin

The following adverse reactions from the labeling for amoxicillin are provided for information:

The most common adverse reactions (>1%) observed in clinical trials of amoxicillin capsules were diarrhea, rash, vomiting and nausea.

The most frequently reported adverse events for patients who received triple therapy (amoxicillin/clarithromycin/lansoprazole) were diarrhea (7%), headache (6%), and taste perversion (5%).

Liver—AST replaces SGOT and ALT replaces SGPT

Clarithromycin

The following adverse reactions from the labeling for clarithromycin are provided for information: The most frequent and common adverse reactions related to clarithromycin therapy for both

adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting, and dysgeusia.

These adverse reactions are consistent with the known safety profile of macrolide antibiotics.

There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.

Adverse Reactions Observed During Clinical Trials of Clarithromycin

The following adverse reactions were observed in clinical trials with clarithromycin at a rate greater than or equal to 1%:

Gastrointestinal Disorders – Diarrhea, vomiting, dyspepsia, nausea, abdominal pain

Hepatobiliary Disorders – Liver function test abnormal

Immune System Disorders – Anaphylactoid reaction

Infections and Infestations – Candidiasis

Nervous System Disorders – Dysgeusia, headache

Psychiatric Disorders – Insomnia

Skin and Subcutaneous Tissue Disorders – Rash

Other Adverse Reactions Observed During Clinical Trials of Clarithromycin

The following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%:

Blood and Lymphatic System Disorders – Leukopenia, neutropenia, thrombocythemia, eosinophilia

Cardiac Disorders – Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations

Ear and Labyrinth Disorders – Vertigo, tinnitus, hearing impaired

Gastrointestinal Disorders – Stomatitis, glossitis, esophagitis, gastroesophageal reflux disease, gastritis, proctalgia, abdominal distention, constipation, dry mouth, eructation, flatulence

General Disorders and Administration Site Conditions – Malaise, pyrexia, asthma, chest pain, chills, fatigue

Hepatobiliary Disorders – Cholestasis, hepatitis

Immune System Disorders – Hypersensitivity

Infections and Infestations – Cellulitis, gastroenteritis, infection, vaginal infection

Investigations – Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal

Metabolism and Nutrition Disorders – Anorexia, decreased appetite

Musculoskeletal and Connective Tissue Disorders – Myalgia, muscle spasms, nuchal rigidity Nervous System Disorders – Dizziness, tremor, loss of consciousness, dyskinesia, somnolence Psychiatric Disorders – Anxiety, nervousness

Renal and Urinary Disorders – Blood creatinine increased, blood urea increased

Respiratory, Thoracic and Mediastinal Disorders – Asthma, epistaxis, pulmonary embolism

Skin and Subcutaneous Tissue Disorders – Urticaria, dermatitis bollus, pruritus, hyperhidrosis, rash maculopapular

The following adverse reactions have been identified during post approval use of clarithromycin. 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.

Blood and Lymphatic System Disorders - Thrombocytopenia, agranulocytosis

Cardiac Disorders – Torsades de pointes, ventricular tachycardia, ventricular arrhythmia

Ear and Labyrinth Disorders - Deafness was reported chiefly in elderly women and was usually reversible.

Gastrointestinal Disorders - Pancreatitis acute, tongue discoloration, tooth discoloration was reported and was usually reversible with professional cleaning upon discontinuation of the drug.

Hepatobiliary Disorders - Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with clarithromycin

Immune System Disorders - Anaphylactic reaction

Infections and Infestations - Pseudomembranous colitis

Investigations - Prothrombin time prolonged, white blood cell count decreased, international normalized ratio increased. Abnormal urine color has been reported, associated with hepatic failure.

Metabolism and Nutrition Disorders - Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin.

Musculoskeletal and Connective Tissue Disorders - Myopathy, rhabdomyolysis was reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicines or allopurinol

Nervous System Disorders - Convulsion, ageusia, parosmia, anosmia, paresthesia

Psychiatric Disorders - Psychotic disorder, confusional state, depersonalization, depression, disorientation, manic behavior, hallucination, abnormal behavior, abnormal dreams. These disorders usually resolve upon discontinuation of the drug.

There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

Renal and Urinary Disorders – Nephritis interstitial, renal failure

Skin and Subcutaneous Tissue Disorders - Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne

Vascular Disorders - Hemorrhage

There have been reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients.

10/24/2016 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

Cutaneous and Systemic Lupus Erythematosus (Added subsection)

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including lansoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving PREVPAC, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

Information for Patients

Patients should be advised to immediately report and seek care for any cardiovascular or neurological symptoms…

Advise patients to report any symptoms associated with cutaneous or systemic lupus erythematosus.

Presence of Gastric Malignancy

In adults, symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy. (Additions and/or revisions underlined)

6 Adverse Reactions

Postmarketing

Body as a Whole – anaphylactic/anaphylactoid reactions, systemic lupus erythematosus

Skin and Appendages – severe dermatologic reactions including erythema multiforme, Stevens- Johnson syndrome, toxic epidermal necrolysis, (some fatal), cutaneous lupus erythematosus.