REPREXAIN™ cannot be expected to substitute for corticosteroids or to treat corticosteroid
insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on
prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to
The pharmacological activity of REPREXAIN™ in reducing fever and inflammation may diminish the
utility of these diagnostic signs in detecting complications of presumed noninfectious, painful
Special Risk Patients
As with any opioid analgesic agent, REPREXAIN™ tablets should be used with caution in elderly or
debilitated patients, and those with severe impairment of hepatic or renal function, hypothyroidism,
Addison's disease, prostatic hypertrophy or urethral stricture. The usual precautions should be
observed and the possibility of respiratory depression should be kept in mind.
Hydrocodone suppresses the cough reflex; as with opioids, caution should be exercised when
REPREXAIN™ is used postoperatively and in patients with pulmonary disease.
Borderline elevations of one or more liver enzymes may occur in up to 15% of patients taking NSAIDs
including ibuprofen as found in REPREXAIN™. These laboratory abnormalities may progress, may
remain essentially unchanged, or may be transient with continued therapy. Notable elevations of SGPT
(ALT) or SGOT (AST) (approximately three or more times the upper limit of normal) have been
reported in approximately 1% of patients in clinical trials with NSAIDS. In addition, rare cases of
severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic
failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test
has occurred, should be evaluated for evidence of the development of more severe hepatic reactions
while on REPREXAIN™ therapy. If clinical signs and symptoms consistent with liver disease develop,
or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), REPREXAIN™ should be
Anemia is sometimes seen in patients receiving NSAIDs including ibuprofen as found in
REPREXAIN™. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely
described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs including
ibuprofen, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.
Patients receiving REPREXAIN™ who may be adversely affected by alterations in platelet function,
such as those with coagulation disorders or patients receiving anticoagulants, should be carefully
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirinsensitive
asthma has been associated with severe bronchospasm, which may be fatal. Since crossreactivity
between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients,
REPREXAIN™ should not be administered to patients with this form of aspirin sensitivity and should
be used with caution in patients with pre-existing asthma.
Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen
therapy as found in REPREXAIN™. Although it is probably more likely to occur in patients with
systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients
who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient
on REPREXAIN™, the possibility of its being related to ibuprofen should be considered.
Information For Patients
Patients should be informed of the following information before initiating therapy with an NSAID
and periodically during the course of ongoing therapy. Patients should also be encouraged to
read the NSAID Medication Guide that accompanies each prescription dispensed.
- REPREXAIN™ (hydrocodone bitartrate and ibuprofen tablets), like other opioid-containing
analgesics, may impair mental and/or physical abilities required for the performance of potentially
hazardous tasks such as driving a car or operating machinery; patients should be cautioned
- Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this
combination product, and should be avoided.
- REPREXAIN™ can be abused in a manner similar to other opioid agonists, legal or illicit.
REPREXAIN™ may be habit-forming. Patients should take the drug only for as long as it is
prescribed, in the amounts prescribed, and no more frequently than prescribed.
- REPREXAIN™, like other NSAID-containing products, may cause serious CV side effects, such as
MI or stroke, which may result in hospitalization and even death. Although serious CV events can
occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain,
shortness of breath, weakness, slurring of speech, and should ask for medical advice when
observing any indicative sign or symptoms. Patients should be apprised of the importance of this
follow-up (see WARNINGS, Cardiovascular Effects ).
- REPREXAIN™, like other NSAID-containing products, can cause GI discomfort and serious GI
side effects, such as ulcers and bleeding, which may result in hospitalization and even death.
Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients
should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia,
melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk Of Ulceration, Bleeding, And Perforation).
- REPREXAIN™, like other NSAID-containing products, can cause serious skin side effects such as
exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although
serious skin reactions may occur without warning, patients should be alert for the signs and
symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and
should ask for medical advice when observing any indicative signs or symptoms. Patients should be
advised to stop the drug immediately if they develop any type of rash and contact their physicians as
soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea,
fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If
these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing,
swelling of the face or throat). If these occur, patients should be instructed to seek immediate
emergency help (see WARNINGS).
- In late pregnancy, as with other NSAIDs, REPREXAIN™ should be avoided because it may cause
premature closure of the ductus arteriosus.
- Patients should be instructed to report any signs of blurred vision or other eye symptoms.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians
should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs
should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash,
etc.) or if abnormal liver tests persist or worsen, REPREXAIN™ should be discontinued.
Carcinogenicity, Mutagenicity, And Impairment Of Fertility
The carcinogenic and mutagenic potential of REPREXAIN™ has not been investigated. The ability of
REPREXAIN™ to impair fertility has not been assessed.
Pregnancy Category C.
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental
REPREXAIN™, administered to rabbits at 95 mg/kg (5.72 and 1.9 times the maximum clinical dose
based on body weight and surface area, respectively), a maternally toxic dose, resulted in an increase in
the percentage of litters and fetuses with any major abnormality and an increase in the number of litters
and fetuses with one or more nonossified metacarpals (a minor abnormality). REPREXAIN™,
administered to rats at 166 mg/kg (10 and 1.66 times the maximum clinical dose based on body weight
and surface area, respectively), a maternally toxic dose, did not result in any reproductive toxicity.
However, animal reproduction studies are not always predictive of human response. There are no
adequate and well-controlled studies in pregnant women. REPREXAIN™ should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of the ductus arteriosus), use during pregnancy (particularly late pregnancy) should be
avoided. Babies born to mothers who have been taking opioids regularly prior to delivery will be
physically dependent. The withdrawal signs include irritability and excessive crying, tremors,
hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and
fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use
or dose. There is no consensus on the best method of managing withdrawal.
Labor And Delivery
As with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and
delayed parturition occurred in rats. Administration of REPREXAIN™ is not recommended during
labor and delivery. The effects of REPREXAIN™ on labor and delivery in pregnant women are
It is not known whether hydrocodone is excreted in human milk. In limited studies, an assay capable of
detecting 1 mcg/mL did not demonstrate ibuprofen in the milk of lactating mothers. However, because of
the limited nature of the studies, and because of the potential for serious adverse reactions in nursing
infants from REPREXAIN™, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of REPREXAIN™ in pediatric patients below the age of 16 have not been
In controlled clinical trials there was no difference in tolerability between patients < 65 years of age
and those ≥ 65, apart from an increased tendency of the elderly to develop constipation. However,
because the elderly may be more sensitive to the renal and gastrointestinal effects of nonsteroidal antiinflammatory
agents as well as possible increased risk of respiratory depression with opioids, extra
caution and reduced dosages should be used when treating the elderly with REPREXAIN™.