Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Severe Cutaneous Adverse Reactions
Additions
and/or revisions underlined:
Severe cutaneous adverse reactions (SCARs)
including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS),
drug reaction with eosinophilia and systemic symptoms (DRESS), and acute
generalized exanthematous pustulosis (AGEP) have been reported with the use of
metronidazole. Symptoms can be serious and potentially life threatening. If
symptoms or signs of SCARs develop,
discontinue PYLERA capsules immediately and institute appropriate therapy.
6
Adverse Reactions
6.3 Other Important Adverse Reactions from Labeling
for the Individual Components of PYLERA
Additions and/or
revisions underlined:
Metronidazole
…
Hypersensitivity/Immune system disorders: Acute generalized exanthematous pustulosis (AGEP) [see Warnings and Precautions (5.5)], urtica ria ,
erythematous rash, flushing, nasal congestion, dryness of the mouth (or vagina
or vulva), and fever [see
Contraindications (4.6)].
Metabolism and
nutrition disorders: Pancreatitis.
Nervous system
disorders: Convulsive
seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy,
headache, syncope, dizziness, vertigo, incoordination, ataxia, tinnitus,
hearing impairment, hearing loss, confusion, dysarthria, irrita bility, depression, weakness, and
insomnia [see Warnings and Precautions
(5.5)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
Severe
Cutaneous Adverse Reactions
Advise
patients that PYLERA capsules may increase the risk of serious and sometimes
fatal dermatologic reactions, including toxic epidermal necrolysis (TEN),
Stevens- Johnson syndrome (SJS), and drug reaction with eosinophilia and
systemic symptoms (DRESS). Instruct the patient to be alert for skin rash,
blisters, fever or other signs and symptoms of these hypersensitivity
reactions. Advise patients to stop PYLERA capsules immediately if they develop
any type of rash and seek medical attention [see Warnings and Precautions (5.5)].
Approved Drug Label (PDF)
4
Contraindications
4.4 Severe Renal Impairment
(Revised subsection title)
4.5 Pregnancy
(Newly added
subsection)
PYLERA is
contraindicated during pregnancy.
5
Warnings and Precautions
5.1 Potential for Carcinogenicity
(Newly added
subsection)
Metronidazole has been shown to be carcinogenic in mice and
rats. Tumors affecting the liver, lungs, mammary and lymphatic tissues have
been detected in several studies of metronidazole in rats and mice, but not
hamsters. It is unknown whether metronidazole is associated with
carcinogenicity in humans.
5.10 Increased Plasma Concentrations in Patients with Hepatic Impairment
(Newly added
subsection)
Patients with hepatic impairment metabolize metronidazole
slowly, with resultant accumulation of metronidazole in the plasma. Use PYLERA
with caution in patients with mild to moderate hepatic impairment. PYLERA may
not be appropriate for patients with severe hepatic impairment (Child-Pugh C).
5.13 Cutaneous Reactions
(Newly added
subsection)
Skin and subcutaneous disorders including Stevens-Johnson
syndrome, toxic epidermal necrolysis and DRESS syndrome (drug rash with
eosinophilia and systemic symptoms) have been reported. Discontinue treatment
at the first evidence of a cutaneous reaction.
5.14 Drug Interactions
(Newly added
subsection)
Oral Contraceptives
Concurrent use of PYLERA with oral contraceptive may make
oral contraceptives less effective due to an interaction with the tetracycline
component of PYLERA. Breakthrough
bleeding has been reported. Advise women
of child-bearing potential to use a different or additional form of
contraception while taking PYLERA.
Anticoagulants
PYLERA may alter the anticoagulant effects of warfarin and
other oral coumarin anticoagulants.
Metronidazole has been reported to potentiate the anticoagulant effect
of warfarin, and other oral coumarin anticoagulants, resulting in a
prolongation of prothrombin time. Tetracycline has been shown to depress plasma
prothrombin activity. Closely monitor prothrombin time, International
Normalized Ratio (INR), or other suitable anticoagulation tests if PYLERA is
administered concomitantly with warfarin. Patients should also be monitored for
evidence of bleeding.
Lithium
In patients
stabilized on relatively high doses
of lithium, short-term use of
PYLERA may cause elevation of
serum lithium concentrations and signs of lithium toxicity due to the
interaction between metronidazole and lithium. Monitor serum lithium and serum
creatinine concentrations daily for several days after beginning treatment with
PYLERA to detect any increase that may precede clinical symptoms of lithium
toxicity.
Busulfan
Metronidazole has been reported to increase plasma
concentrations of busulfan, which can result in an increased risk for serious busulfan
toxicity. Do not administer PYLERA concomitantly with busulfan unless the
benefit outweighs the risk. If no therapeutic alternatives to PYLERA are
available, and concomitant administration with busulfan is medically needed,
Monitor for busulfan toxicity and busulfan plasma concentrations and adjust the
busulfan dose accordingly.
5.2 Fetal Toxicity
(Additions and/or revisions are underlined)
Based on animal data, use of drugs of the
tetracycline class during the second and third trimester of pregnancy can cause
permanent discoloration of the teeth (yellow-gray brown) and possibly inhibit
bone development.
5.5 Central and Peripheral Nervous System Effects
(Additions and/or revisions are underlined)
Metronidazole: Convulsive seizures, encephalopathy,
aseptic meningitis and peripheral neuropathy (including optic neuropathy)
have been reported.
Tetracycline: Intracranial hypertension (IH),
including pseudotumor cerebri, has been associated with the use of
tetracyclines. Clinical manifestations of IH include headache, blurred
vision, diplopia, and vision loss; papilledema can be found on fundoscopy.
Women of childbearing age who are overweight or have a history of IH are at
greater risk for developing tetracycline associated IH. Concomitant use of
isotretinoin should be avoided because isotretinoin is also known to cause IH.
Although IH typically resolves after discontinuation
of treatment, the possibility for permanent visual loss exists. If
visual disturbance occurs during treatment, prompt ophthalmologic evaluation is
warranted. Since intracranial pressure can remain elevated for weeks after drug
cessation, patients should be monitored until they stabilize.
5.6 Development of Potential for Microbial Overgrowth
(Revised subsection title)
6
Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions are underlined)
Infections
and infestations: candidiasis, pseudomembranous colitis (Clostridium difficile colitis).
Nervous
Systems: peripheral neuropathy.
Skin
and subcutaneous disorders: Stevens-Johnson syndrome, toxic
epidermal necrolysis, DRESS syndrome (drug rash with eosinophilia and systemic
symptoms)
6.3 Other Important Adverse Reactions from Labeling for the Individual Components of PYLERA
(Additions and/or revisions are underlined)
Metronidazole
Gastrointestinal
disorders: Nausea, vomiting, diarrhea, abdominal pain, constipation,
anorexia, metallic taste, furry tongue, glossitis, stomatitis and
candida overgrowth.
Hypersensitivity/Immune
system disorders: Urticaria, erythematous rash, flushing, nasal congestion,
dryness of the mouth (or vagina or vulva), and fever.
Nervous system
disorders: Convulsive seizures, encephalopathy, aseptic meningitis, optic
and peripheral neuropathy, headache, syncope, dizziness, vertigo,
incoordination, ataxia, confusion, dysarthria, irritability, depression,
weakness, and insomnia.
Dermatologic
disorders: Erythematous rash and pruritus.
Renal and urinary
disorders: Dysuria, cystitis, polyuria, incontinence, darkened urine,
and a sense of pelvic pressure.
Other: Dyspareunia,
decrease of libido, proctitis, joint pains.
Tetracycline
Hydrochloride
Gastrointestinal
disorders: Nausea, vomiting, diarrhea, anorexia, glossitis, black
hairy tongue, dysphagia, enterocolitis, inflammatory lesions (with Candida
overgrowth) in the anogenital region, esophagitis and esophageal ulceration.
Skin and subcutaneous
tissue disorders: Maculopapular and erythematous rashes, onycholysis,
discoloration of the nails, exfoliative dermatitis and photosensitivity
have been rarely reported.
Liver:
Hepatotoxicity and liver failure.
Hypersensitivity
reactions: Urticaria, angioedema, anaphylaxis,
Henoch-Schonlein purpura, pericarditis, exacerbation of systemic lupus erythematosus,
and serum sickness-like reactions.
7
Drug Interactions
7.8 Busulfan
(Newly added
subsection)
Metronidazole has been reported to increase plasma
concentrations of busulfan, which can result in an increased risk for serious busulfan
toxicity. Do not administer PYLERA concomitantly with busulfan unless the
benefit outweighs the risk. If no therapeutic alternatives to PYLERA are
available, and concomitant administration with busulfan is medically needed,
monitor for busulfan toxicity and busulfan plasma concentrations and adjust the
busulfan dose accordingly.
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR)
Conversion; Additions and/or revisions are underlined)
Risk Summary
PYLERA is contraindicated in women who are
pregnant because treatment of Helicobacter
pylori infection can be delayed in pregnant women, and the
use of drugs of the tetracycline class during the second and
third trimester pregnancy can also cause permanent discoloration of the
teeth (yellow-gray brown) and possibly inhibit bone development. Administration of oral tetracycline to
pregnant rats at various doses resulted in yellow fluorescence in teeth
and bones in the newborn animals. There are maternal risks with high
intravenous doses of tetracycline. Metronidazole usage in pregnancy has been
associated with certain congenital anomalies.
In animals, no fetotoxicity was observed when metronidazole was orally
administered to pregnant Themice at approximately 5% of the indicated
human dose. There are no human or animal data on the use of bismuth
subcitrate potassium during pregnancy. Although there are data on the separate
components, there are no available data on the use of PYLERA in pregnant women.
Clinical Considerations
Maternal Adverse
Reactions
Tetracycline administered during pregnancy at high doses
(> 2 g IV) was associated with rare but serious cases of maternal
hepatotoxicity. This syndrome may result in stillborn or premature birth due to
maternal pathology.
Data
Human Data
Bismuth subcitrate potassium
There are no human data on the use of bismuth subcitrate
potassium during pregnancy.
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR)
Conversion; Additions and/or revisions are underlined)
Risk Summary
Two of the individual components of PYLERA,
tetracycline and metronidazole, are present in human milk at concentrations
similar to maternal serum levels. It is not known whether bismuth subcitrate,
the third component of PYLERA is present in human milk. It is not known what
effect metronidazole, tetracycline or bismuth has on the breastfed
infant or on milk production…Metronidazole
transfers to human milk, and infant serum levels can be close to or comparable
to infant therapeutic levels. Because of the potential risk of tumorigenicity
shown in animal studies with metronidazole, a woman should pump and discard
human milk for the duration of PYLERA therapy, and for 2 days after therapy
ends, and feed her infant stored human milk (collected prior to therapy) or
formula.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions are underlined)
Lactation
Advise the lactating women
to pump and discard their milk during treatment with PYLERA
and for 2 days after the therapy ends.
Drug Interactions
Dosing Information
If a dose is missed, advise patient not to make up the
dose, but to continue the normal dosing schedule until medication is gone. Patients
should not take double doses. If more than 4 doses are missed, advise the patient
to contact their health-care provider
Distributed By: Allergan USA, Inc. Irvine,
CA 92612
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