Tegretol


Generic Name: carbamazepine
Dosage Form: chewable tablets, tablets, extended release tablets and oral suspension
Tegretol

Tegretol®

carbamazepine USP

Chewable Tablets of 100 mg - red-speckled, pink

Tablets of 200 mg – pink

Suspension of 100 mg/5 mL

Tegretol®-XR

(carbamazepine extended-release tablets)

100 mg, 200 mg, 400 mg

Rx only

Prescribing Information

WARNINGS

SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE

SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH Tegretol. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH Tegretol. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH Tegretol UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, LABORATORY TESTS).

APLASTIC ANEMIA AND AGRANULOCYTOSIS

APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF Tegretol. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5-8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.

ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF Tegretol, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.

BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON Tegretol ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.

Before prescribing Tegretol, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential.

DESCRIPTION

Tegretol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as chewable tablets of 100 mg, tablets of 200 mg, XR tablets of 100, 200, and 400 mg, and as a suspension of 100 mg/5 mL (teaspoon). Its chemical name is 5H-dibenz[b,f ]azepine-5-carboxamide, and its structural formula is

Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone. Its molecular weight is 236.27.

Inactive Ingredients Tablets: Colloidal silicon dioxide, D&C Red No. 30 Aluminum Lake (chewable tablets only), FD&C Red No. 40 (200-mg tablets only), flavoring (chewable tablets only), gelatin, glycerin, magnesium stearate, sodium starch glycolate (chewable tablets only), starch, stearic acid, and sucrose (chewable tablets only). Suspension: Citric acid, FD&C Yellow No. 6, flavoring, polymer, potassium sorbate, propylene glycol, purified water, sorbitol, sucrose, and xanthan gum. Tegretol-XR tablets: cellulose compounds, dextrates, iron oxides, magnesium stearate, mannitol, polyethylene glycol, sodium lauryl sulfate, titanium dioxide (200-mg tablets only).

CLINICAL PHARMACOLOGY

In controlled clinical trials, Tegretol has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Mechanism of Action

Tegretol has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Tegretol greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Tegretol is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.

The principal metabolite of Tegretol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Tegretol has not been established.

Pharmacokinetics

In clinical studies, Tegretol suspension, conventional tablets, and XR tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, Tegretol suspension affords steady-state plasma levels comparable to Tegretol tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, Tegretol-XR tablets afford steady-state plasma levels comparable to conventional Tegretol tablets given q.i.d., when administered at the same total mg daily dose. Tegretol in blood is 76% bound to plasma proteins. Plasma levels of Tegretol are variable and may range from 0.5-25 µg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 µg/mL. In polytherapy, the concentration of Tegretol and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4-5 hours after administration of conventional Tegretol tablets, and 3-12 hours after administration of Tegretol-XR tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound Tegretol in serum. Because Tegretol induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3-5 weeks of a fixed dosing regimen. Initial half-life values range from 25-65 hours, decreasing to 12-17 hours on repeated doses. Tegretol is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from Tegretol. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Tegretol.

The pharmacokinetic parameters of Tegretol disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and Tegretol dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10-15 years of age).

The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.

INDICATIONS AND USAGE Epilepsy

Tegretol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of Tegretol as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:

Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types.
Generalized tonic-clonic seizures (grand mal).
Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by Tegretol (see PRECAUTIONS, General). Trigeminal Neuralgia

Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia.

Beneficial results have also been reported in glossopharyngeal neuralgia.

This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.

CONTRAINDICATIONS

Tegretol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of Tegretol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated.

WARNINGS Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with Tegretol treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Tegretol should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

SJS/TEN and HLA-B*1502 Allele

Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.

Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in <1% of the population in Japan and Korea.

HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).

Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS, Laboratory Tests).

Over 90% of Tegretol treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on Tegretol.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from Tegretol, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).

Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable.

Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated with Tegretol will not develop SJS/TEN, and these reactions can still occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Aplastic Anemia and Agranulocytosis

Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Tegretol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients
Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients
Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Tegretol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

General

Tegretol has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy.

Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

The use of Tegretol should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving Tegretol therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

As with all antiepileptic drugs, Tegretol should be withdrawn gradually to minimize the potential of increased seizure frequency.

Usage in Pregnancy

Carbamazepine can cause fetal harm when administered to a pregnant woman.

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. In treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.

In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.

Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.

Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal Tegretol and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Tegretol use. These symptoms may represent a neonatal withdrawal syndrome.

To provide information regarding the effects of in utero exposure to Tegretol, physicians are advised to recommend that pregnant patients taking Tegretol enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

PRECAUTIONS General

Before initiating therapy, a detailed history and physical examination should be made.

Tegretol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients Tegretol has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE).

Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with Tegretol.

AV heart block, including second and third degree block, have been reported following Tegretol treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances.

Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug.

Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases (see ADVERSE REACTIONS, Other and PRECAUTIONS, Information for Patients).

Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.

Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If positive, caution should be used in prescribing carbamazepine.

In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine (Trileptal®).

Since a given dose of Tegretol suspension will produce higher peak levels than the same dose given as the tablet, it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).

Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance.

Information for Patients

Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking Tegretol.

Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use.

Patients, their caregivers, and families should be counseled that AEDs, including Tegretol, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers

Patients should be advised that serious skin reactions have been reported in association with Tegretol. In the event a skin reaction should occur while taking Tegretol, patients should consult with their physician immediately (see WARNINGS).

Tegretol may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription medications or herbal products.

Caution should be exercised if alcohol is taken in combination with Tegretol therapy, due to a possible additive sedative effect.

Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks.

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy subsection).

Laboratory Tests

For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.

Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.

Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.

Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes.

Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction.

Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used.

Thyroid function tests have been reported to show decreased values with Tegretol administered alone.

Hyponatremia has been reported in association with Tegretol use, either alone or in combination with other drugs.

Interference with some pregnancy tests has been reported.

Drug Interactions

There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Tegretol suspension immediately followed by Thorazine®* solution. Subsequent testing has shown that mixing Tegretol suspension and chlorpromazine solution (both generic and brand name) as well as Tegretol suspension and liquid Mellaril® resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known, Tegretol suspension should not be administered simultaneously with other liquid medicinal agents or diluents (see DOSAGE AND ADMINISTRATION).

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

Agents That May Affect Tegretol Plasma Levels

CYP 3A4 inhibitors inhibit Tegretol metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include:
      cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine,
      fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine,
      omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene,
      azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil,
      ticlopidine, grapefruit juice, protease inhibitors, valproate*.

CYP 3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include:
      cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone,
      methsuximide, theophylline, aminophylline.

When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

*increased levels of the active 10,11-epoxide

†decreased levels of carbamazepine and increased levels of the 10,11-epoxide

Effect of Tegretol on Plasma Levels of Concomitant Agents

Increased levels: clomipramine HCl, phenytoin, primidone

Tegretol is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of co-medications mainly metabolized by 3A4 through induction of their metabolism. Tegretol causes, or would be expected to cause, decreased levels of the following:

      acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine),
      citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine,
      dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine,
      levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal
      contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors,
      risperidone, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g.,
      imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.

In concomitant use with Tegretol, dosage adjustment of the above agents may be necessary.

Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS).

Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.

Concomitant medication with Tegretol and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.

Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium).

Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.

Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.

Concomitant use of Tegretol with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.

Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.

Usage in Pregnancy

Pregnancy Category D (see WARNINGS).

Labor and Delivery

The effect of Tegretol on human labor and delivery is unknown.

Nursing Mothers

Tegretol and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for Tegretol and about 0.5 for the epoxide. The estimated doses given to the newborn during breast-feeding are in the range of 2-5 mg daily for Tegretol and 1-2 mg daily for the epoxide.

Because of the potential for serious adverse reactions in nursing infants from carbamazepine, 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.

Pediatric Use

Substantial evidence of Tegretol’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.

Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e., 4-12 mcg/mL) is the same in children and adults.

The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available.

Geriatric Use

No systematic studies in geriatric patients have been conducted.

ADVERSE REACTIONS

If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards.

The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED WARNING), the liver, and the cardiovascular system.

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the low dosage recommended.

The following additional adverse reactions have been reported:

Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda.

Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXED WARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.

Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.

Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure.

Pancreatic: Pancreatitis.

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.

Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

Testicular atrophy occurred in rats receiving Tegretol orally from 4-52 weeks at dosage levels of 50-400 mg/kg/day. Additionally, rats receiving Tegretol in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.

Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome.

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.

Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs.

Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.

Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes.

Musculoskeletal System: Aching joints and muscles, and leg cramps.

Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with Tegretol use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium leading to osteoporosis have been reported.

Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and abnormal liver function tests. These signs and symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and PRECAUTIONS, Information for Patients).

Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

DRUG ABUSE AND DEPENDENCE

No evidence of abuse potential has been associated with Tegretol, nor is there evidence of psychological or physical dependence in humans.

OVERDOSAGE

Acute Toxicity

Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).

Oral LD50 in animals (mg/kg): mice, 1100-3750; rats, 3850-4025; rabbits, 1500-2680; guinea pigs, 920.

Signs and Symptoms

The first signs and symptoms appear after 1-3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (>60 g) have been ingested.

Respiration: Irregular breathing, respiratory depression.

Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.

Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.

Gastrointestinal Tract: Nausea, vomiting.

Kidneys and Bladder: Anuria or oliguria, urinary retention.

Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias.

Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with Tegretol may be aggravated or modified.

Treatment

The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigating the stomach, and by taking appropriate steps to diminish absorption. If these measures cannot be implemented without risk on the spot, the patient should be transferred at once to a hospital, while ensuring that vital functions are safeguarded. There is no specific antidote.

Elimination of the Drug: Induction of vomiting.

Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug, the stomach should be repeatedly irrigated, especially if the patient has also consumed alcohol.

Measures to Reduce Absorption: Activated charcoal, laxatives.

Measures to Accelerate Elimination: Forced diuresis.

Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children.

Respiratory Depression: Keep the airways free; resort, if necessary, to endotracheal intubation, artificial respiration, and administration of oxygen.

Hypotension, Shock: Keep the patient’s legs raised and administer a plasma expander. If blood pressure fails to rise despite measures taken to increase plasma volume, use of vasoactive substances should be considered.

Convulsions: Diazepam or barbiturates.

Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children), hypotension, and coma. However, barbiturates should not be used if drugs that inhibit monoamine oxidase have also been taken by the patient either in overdosage or in recent therapy (within 1 week).

Surveillance: Respiration, cardiac function (ECG monitoring), blood pressure, body temperature, pupillary reflexes, and kidney and bladder function should be monitored for several days.

Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops, the following recommendations are suggested: (1) stop the drug, (2) perform daily CBC, platelet, and reticulocyte counts, (3) do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery.

Special periodic studies might be helpful as follows: (1) white cell and platelet antibodies, (2) 59Fe-ferrokinetic studies, (3) peripheral blood cell typing, (4) cytogenetic studies on marrow and peripheral blood, (5) bone marrow culture studies for colony-forming units, (6) hemoglobin electrophoresis for A2 and F hemoglobin, and (7) serum folic acid and B12 levels.


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Epitol


carbamazepine
Dosage Form: tablet
Epitol®
CARBAMAZEPINE TABLETS USP, 200 mg
0090
Rx only

Prescribing Information

WARNINGS

SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE

SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE BEEN REPORTED DURING TREATMENT WITH CARBAMAZEPINE. THESE REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH CARBAMAZEPINE. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH CARBAMAZEPINE UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK (SEE WARNINGS AND PRECAUTIONS, Laboratory Tests).

APLASTIC ANEMIA AND AGRANULOCYTOSIS

APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF CARBAMAZEPINE. DATA FROM A POPULATION-BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING THESE REACTIONS IS 5 TO 8 TIMES GREATER THAN IN THE GENERAL POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.

ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF CARBAMAZEPINE, DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.

BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON CARBAMAZEPINE ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS.

Before prescribing Epitol®, the physician should be thoroughly familiar with the details of this prescribing information, particularly regarding use with other drugs, especially those which accentuate toxicity potential.

Epitol Description

Epitol, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal neuralgia, available for oral administration as tablets of 200 mg. Its chemical name is 5H-dibenz[b,f]azepine-5-carboxamide, and its structural formula is:

C15H12N2O M.W. 236.27

Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in alcohol and in acetone.

Epitol 200 mg tablets contain the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, ethylcellulose, glycerin, lactose monohydrate, magnesium stearate, and sodium starch glycolate.

Epitol 200 mg tablets meet USP Dissolution Test 3.

Epitol - Clinical Pharmacology

In controlled clinical trials, carbamazepine has been shown to be effective in the treatment of psychomotor and grand mal seizures, as well as trigeminal neuralgia.

Mechanism of Action

Carbamazepine has demonstrated anticonvulsant properties in rats and mice with electrically and chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the post-tetanic potentiation. Carbamazepine greatly reduces or abolishes pain induced by stimulation of the infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes, including the linguomandibular reflex in cats. Carbamazepine is chemically unrelated to other anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action remains unknown.

The principal metabolite of Epitol, carbamazepine-10,11-epoxide, has anticonvulsant activity as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide has been postulated, the significance of its activity with respect to the safety and efficacy of Epitol has not been established.

Pharmacokinetics

In clinical studies, carbamazepine suspension, conventional tablets, and extended-release tablets delivered equivalent amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster, and the extended-release tablet slightly slower, than the conventional tablet. The bioavailability of the extended-release tablet was 89% compared to suspension. Following a b.i.d. dosage regimen, the suspension provides higher peak levels and lower trough levels than those obtained from the conventional tablet for the same dosage regimen. On the other hand, following a t.i.d. dosage regimen, carbamazepine suspension affords steady-state plasma levels comparable to carbamazepine tablets given b.i.d. when administered at the same total mg daily dose. Following a b.i.d. dosage regimen, carbamazepine extended-release tablets afford steady-state plasma levels comparable to conventional carbamazepine tablets given q.i.d., when administered at the same total mg daily dose. Carbamazepine in blood is 76% bound to plasma proteins. Plasma levels of carbamazepine are variable and may range from 0.5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of carbamazepine and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered (see PRECAUTIONS, Drug Interactions). Following chronic oral administration of suspension, plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of conventional carbamazepine tablets, and 3 to 12 hours after administration of carbamazepine extended-release tablets. The CSF/serum ratio is 0.22, similar to the 24% unbound carbamazepine in serum. Because carbamazepine induces its own metabolism, the half-life is also variable. Autoinduction is completed after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours, decreasing to 12 to 17 hours on repeated doses. Carbamazepine is metabolized in the liver. Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of carbamazepine-10,11-epoxide from carbamazepine. After oral administration of 14C-carbamazepine, 72% of the administered radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed largely of hydroxylated and conjugated metabolites, with only 3% of unchanged carbamazepine.

The pharmacokinetic parameters of carbamazepine disposition are similar in children and in adults. However, there is a poor correlation between plasma concentrations of carbamazepine and carbamazepine dose in children. Epitol is more rapidly metabolized to carbamazepine-10,11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below the age of 1 year to 0.18 in children between 10 to 15 years of age).

The effects of race and gender on carbamazepine pharmacokinetics have not been systematically evaluated.

Indications and Usage for Epitol Epilepsy

Epitol is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled patients with the following seizure types:

Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvement than those with other types. Generalized tonic-clonic seizures (grand mal). Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by carbamazepine (see PRECAUTIONS, General). Trigeminal Neuralgia

Epitol is indicated in the treatment of the pain associated with true trigeminal neuralgia.

Beneficial results have also been reported in glossopharyngeal neuralgia.

This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.

Contraindications

Epitol should not be used in patients with a history of previous bone marrow depression, hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds its use with monoamine oxidase inhibitors is not recommended. Before administration of Epitol, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits.

Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated.

Warnings Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations. However, the risk in some Asian countries is estimated to be about 10 times higher. Carbamazepine should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

SJS/TEN and HLA-B*1502 Allele

Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity.

Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than 15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in some groups. HLA-B*1502 is present in < 1% of the population in Japan and Korea.

HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans).

Prior to initiating carbamazepine therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Carbamazepine should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS, Laboratory Tests).

Over 90% of carbamazepine treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. This information may be taken into consideration in determining the need for screening of genetically at-risk patients currently on carbamazepine.

The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous reactions from carbamazepine, such as anticonvulsant hypersensitivity syndrome or nonserious rash (maculopapular eruption [MPE]).

Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Chinese ancestry taking other antiepileptic drugs associated with SJS/TEN. Consideration should be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable.

Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian patients treated with carbamazepine will not develop SJS/TEN, and these reactions can still occur infrequently in HLA-B*1502-negative patients of any ethnicity. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.

Aplastic Anemia and Agranulocytosis

Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Epitol, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Epitol or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

General

Carbamazepine has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy.

Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a latent psychosis and, in elderly patients, of confusion or agitation should be borne in mind.

The use of carbamazepine should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving carbamazepine therapy. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

As with all antiepileptic drugs, Epitol should be withdrawn gradually to minimize the potential of increased seizure frequency.

Usage in Pregnancy

Carbamazepine can cause fetal harm when administered to a pregnant woman.

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. There have also been reports that associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial defects, cardiovascular malformations, hypospadias and anomalies involving various body systems). Developmental delays based on neurobehavioral assessments have been reported. In treating or counseling women of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against the risks. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.

In humans, transplacental passage of carbamazepine is rapid (30 to 60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.

Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10 to 25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg basis or 1.5 to 4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200 mg/kg.

Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

Tests to detect defects using currently accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal Epitol use. These symptoms may represent a neonatal withdrawal syndrome.

To provide information regarding the effects of in utero exposure to Epitol, physicians are advised to recommend that pregnant patients taking Epitol enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Precautions General

Before initiating therapy, a detailed history and physical examination should be made.

Epitol should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures, since in these patients carbamazepine has been associated with increased frequency of generalized convulsions (see INDICATIONS AND USAGE).

Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance, including second and third degree AV heart block; cardiac, hepatic, or renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to other anticonvulsants; or interrupted courses of therapy with carbamazepine.

AV heart block, including second and third degree block, have been reported following carbamazepine treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk factors for conduction disturbances.

Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported (see ADVERSE REACTIONS and PRECAUTIONS, Laboratory Tests). In some cases, hepatic effects may progress despite discontinuation of the drug.

Multiorgan hypersensitivity reactions which can affect the skin, liver, hemopoietic organs and lymphatic system or other organs and occurring days to weeks or months after initiating treatment have been reported in rare cases (see ADVERSE REACTIONS, Otherand PRECAUTIONS, Information for Patients).

Discontinuation of carbamazepine should be considered if any evidence of hypersensitivity develops.

Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin and phenobarbital. A history of hypersensitivity reactions should be obtained for a patient and the immediate family members. If positive, caution should be used in prescribing carbamazepine.

In patients who have exhibited hypersensitivity reactions to carbamazepine approximately 25 to 30% of these patients may experience hypersensitivity reactions with oxcarbazepine.

Information for Patients

Patients should be informed of the availability of a Medication Guide and they should be instructed to read the Medication Guide before taking Epitol.

Patients should be made aware of the early toxic signs and symptoms of a potential hematologic problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use.

Patients, their caregivers, and families should be counseled that AEDs, including Epitol, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be advised that serious skin reactions have been reported in association with Epitol. In the event a skin reaction should occur while taking Epitol, patients should consult with their physician immediately (see WARNINGS).

Carbamazepine may interact with some drugs. Therefore, patients should be advised to report to their doctors the use of any other prescription or nonprescription medications or herbal products.

Caution should be exercised if alcohol is taken in combination with carbamazepine therapy, due to a possible additive sedative effect.

Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks.

Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy).

Laboratory Tests

For genetically at-risk patients (see WARNINGS), high-resolution 'HLA-B*1502 typing' is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.

Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.

Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur (see PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued, based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.

Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are recommended since many phenothiazines and related drugs have been shown to cause eye changes.

Baseline and periodic complete urinalysis and BUN determinations are recommended for patients treated with this agent because of observed renal dysfunction.

Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in determining the cause of toxicity when more than one medication is being used.

Thyroid function tests have been reported to show decreased values with carbamazepine administered alone.

Hyponatremia has been reported in association with carbamazepine use, either alone or in combination with other drugs.

Interference with some pregnancy tests has been reported.

Drug Interactions

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to, the following:

Agents That May Affect Carbamazepine Plasma Levels

CYP 3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include:

cimetidine, danazol, diltiazem, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, nefazodone, trazodone, loxapine*, olanzapine, quetiapine*, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketoconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, protease inhibitors, valproate*.

CYP 3A4 inducers can increase the rate of carbamazepine metabolism. Drugs that have been shown, or that would be expected, to decrease plasma carbamazepine levels include:

cisplatin, doxorubicin HCl, felbamate†, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline.

When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.

* increased levels of the active 10,11-epoxide 

† decreased levels of carbamazepine and increased levels of the 10,11-epoxide

Effect of Carbamazepine on Plasma Levels of Concomitant Agents

Increased levels: clomipramine HCl, phenytoin, primidone

Carbamazepine is a potent inducer of hepatic CYP 3A4 and may therefore reduce plasma concentrations of comedications mainly metabolized by 3A4 through induction of their metabolism. Carbamazepine causes, or would be expected to cause, decreased levels of the following:

acetaminophen, alprazolam, bupropion, dihydropyridine calcium channel blockers (e.g., felodipine), citalopram, cyclosporine, corticosteroids (e.g., prednisolone, dexamethasone), clonazepam, clozapine, dicumarol, doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.

In concomitant use with carbamazepine, dosage adjustment of the above agents may be necessary.

Coadministration of carbamazepine with nefazodone results in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine with nefazodone is contraindicated (see CONTRAINDICATIONS).

Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.

Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity. Concomitant medication with carbamazepine and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia. Carbamazepine may antagonize the effects of nondepolarizing muscle relaxants (e.g., pancuronium). Their dosage may need to be raised, and patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected.

Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.

Concomitant use of carbamazepine with hormonal contraceptive products (e.g., oral, and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Breakthrough bleeding and unintended pregnancies have been reported. Alternative or back-up methods of contraception should be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carbamazepine, when administered to Sprague-Dawley rats for two years in the diet at doses of 25, 75, and 250 mg/kg/day, resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.

Carbamazepine must, therefore, be considered to be carcinogenic in Sprague-Dawley rats. Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results. The significance of these findings relative to the use of carbamazepine in humans is, at present, unknown.

Usage in Pregnancy Teratogenic Effects Pregnancy category D

(See WARNINGS.)

Labor and Delivery

The effect of carbamazepine on human labor and delivery is unknown.

Nursing Mothers

Carbamazepine and its epoxide metabolite are transferred to breast milk. The ratio of the concentration in breast milk to that in maternal plasma is about 0.4 for carbamazepine and about 0.5 for the epoxide. The estimated doses given to the newborn during breast-feeding are in the range of 2 to 5 mg daily for carbamazepine and 1 to 2 mg daily for the epoxide.

Because of the potential for serious adverse reactions in nursing infants from carbamazepine, 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.

Pediatric Use

Substantial evidence of carbamazepine’s effectiveness for use in the management of children with epilepsy (see INDICATIONS AND USAGE for specific seizure types) is derived from clinical investigations performed in adults and from studies in several in vitro systems which support the conclusion that (1) the pathogenetic mechanisms underlying seizure propagation are essentially identical in adults and children, and (2) the mechanism of action of carbamazepine in treating seizures is essentially identical in adults and children.

Taken as a whole, this information supports a conclusion that the generally accepted therapeutic range of total carbamazepine in plasma (i.e., 4 to 12 mcg/mL) is the same in children and adults.

The evidence assembled was primarily obtained from short-term use of carbamazepine. The safety of carbamazepine in children has been systematically studied up to 6 months. No longer-term data from clinical trials is available.

Geriatric Use

No systematic studies in geriatric patients have been conducted.

Adverse Reactions

If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards.

The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXEDWARNING), the liver, and the cardiovascular system.

The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the low dosage recommended.

The following additional adverse reactions have been reported:

Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, anemia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda.

Skin: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) (see BOXEDWARNING), pruritic and erythematous rashes, urticaria, photosensitivity reactions, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, and diaphoresis. In certain cases, discontinuation of therapy may be necessary. Isolated cases of hirsutism have been reported, but a causal relationship is not clear.

Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy.

Some of these cardiovascular complications have resulted in fatalities. Myocardial infarction has been associated with other tricyclic compounds.

Liver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis; very rare cases of hepatic failure.

Pancreatic: Pancreatitis.

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia.

Genitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported. There have been very rare reports of impaired male fertility and/or abnormal spermatogenesis.

Testicular atrophy occurred in rats receiving carbamazepine orally from 4 to 52 weeks at dosage levels of 50 to 400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis. In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown.

Nervous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome.

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established.

Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs.

Digestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.

Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure as well as conjunctivitis, have been reported. Although a direct causal relationship has not been established, many phenothiazines and related drugs have been shown to cause eye changes.

Musculoskeletal System: Aching joints and muscles, and leg cramps.

Metabolism: Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome has been reported. Cases of frank water intoxication, with decreased serum sodium (hyponatremia) and confusion, have been reported in association with carbamazepine use (see PRECAUTIONS, Laboratory Tests). Decreased levels of plasma calcium leading to osteoporosis have been reported.

Other: Multiorgan hypersensitivity reactions occurring days to weeks or months after initiating treatment have been reported in rare cases. Signs or symptoms may include, but are not limited to fever, skin rashes, vasculitis, lymphadenopathy, disorders mimicking lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and abnormal liver function tests. These signs and symptoms may occur in various combinations and not necessarily concurrently. Signs and symptoms may initially be mild. Various organs, including but not limited to, liver, skin, immune system, lungs, kidneys, pancreas, myocardium, and colon may be affected (see PRECAUTIONS, General and PRECAUTIONS, Information for Patients).

Isolated cases of a lupus erythematosus-like syndrome have been reported. There have been occasional reports of elevated levels of cholesterol, HDL cholesterol, and triglycerides in patients taking anticonvulsants.

A case of aseptic meningitis, accompanied by myoclonus and peripheral eosinophilia, has been reported in a patient taking carbamazepine in combination with other medications. The patient was successfully dechallenged, and the meningitis reappeared upon rechallenge with carbamazepine.

Drug Abuse and Dependence

No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.

Overdosage Acute Toxicity

Lowest known lethal dose: adults, 3.2 g (a 24-year-old woman died of a cardiac arrest and a 24-year-old man died of pneumonia and hypoxic encephalopathy); children, 4 g (a 14-year-old girl died of a cardiac arrest), 1.6 g (a 3-year-old girl died of aspiration pneumonia).

Oral LD50 in animals (mg/kg): mice, 1100 to 3750; rats, 3850 to 4025; rabbits, 1500 to 2680; guinea pigs, 920.

Signs and Symptoms

The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder, and severe cardiac complications occur only when very high doses (> 60 g) have been ingested.

Respiration: Irregular breathing, respiratory depression.

Cardiovascular System: Tachycardia, hypotension or hypertension, shock, conduction disorders.

Nervous System and Muscles: Impairment of consciousness ranging in severity to deep coma. Convulsions, especially in small children. Motor restlessness, muscular twitching, tremor, athetoid movements, opisthotonos, ataxia, drowsiness, dizziness, mydriasis, nystagmus, adiadochokinesia, ballism, psychomotor disturbances, dysmetria. Initial hyperreflexia, followed by hyporeflexia.

Gastrointestinal Tract: Nausea, vomiting.

Kidneys and Bladder: Anuria or oliguria, urinary retention.

Laboratory Findings: Isolated instances of overdosage have included leukocytosis, reduced leukocyte count, glycosuria, and acetonuria. EEG may show dysrhythmias.

Combined Poisoning: When alcohol, tricyclic antidepressants, barbiturates, or hydantoins are taken at the same time, the signs and symptoms of acute poisoning with carbamazepine may be aggravated or modified.

Treatment

The prognosis in cases of severe poisoning is critically dependent upon prompt elimination of the drug, which may be achieved by inducing vomiting, irrigatin


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Boots Bite & Sting Relief 2 Years Plus Antihistamine Cream


Boots Bite & Sting Relief 2 Years Plus Antihistamine Cream

(Mepyramine Maleate)

From 2 years

Relieves pain, itching and swelling

20 g e

Read all of this carton for full instructions.

What this medicine is for

A soothing antihistamine cream for the relief of pain, itching and swelling caused by insect bites and stings, and nettle stings.

Before you use this medicine X Do not use: If you are allergic to any of the ingredients or other antihistamines If you have eczema or other skin conditions If you are pregnant or breastfeeding, unless your doctor tells you to On broken skin, sunburnt skin or on large areas of skin

Cetostearyl alcohol and lanolin may cause skin reactions (e.g. contact dermatitis).

How to use this medicine

Check the tube seal is not broken before first use. If it is, do not use the cream. Pierce tube seal with end of cap.

Apply to the skin only.

Adults and children of 2 years and over:

Smooth a very small amount on the affected area. Use the cream 2 or 3 times a day, for a maximum of 3 days.

Do not use on children under 2 years.

If a rash develops, or the condition gets worse, stop using the cream.

If symptoms do not go away talk to your doctor.

! If anyone accidentally swallows some:

Talk to a doctor straight away.

Possible side effects

Most people will not have problems.

If you get these side effects stop using the cream and see a doctor.

Allergic reaction (e.g. skin rash, red or itchy skin, worsening of the condition you are treating)

If you notice any side effect not listed here, please tell your pharmacist or doctor.

How to store this medicine

Do not store above 25°C.

Keep all medicines out of the sight and reach of children.

Use by the date on the end flap of the carton.

Active ingredient

This cream contains Mepyramine Maleate 2% w/w.

Also contains: purified water, cetostearyl alcohol, white soft paraffin, liquid paraffin, cetomacrogol 1000, anhydrous hypoallergenic lanolin, sorbitan sesquioleate, sodium citrate, citric acid monohydrate.

PL 00014/0440

Text prepared 2/07

Manufactured by the Marketing Authorisation holder The Boots Company PLC Nottingham NG2 3AA

If you need more advice ask your pharmacist.

BTC14991 vD 15-06-07


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Family Meltus Chesty Coughs Honey & Lemon Flavour


1. Name Of The Medicinal Product

Family Meltus Chesty Coughs Honey and Lemon Flavour

2. Qualitative And Quantitative Composition

Guaifenesin BP 50.00mg/5ml.

3. Pharmaceutical Form

Syrup.

4. Clinical Particulars 4.1 Therapeutic Indications

Symptomatic relief of deep chesty coughs and to soothe the throat.

4.2 Posology And Method Of Administration

Route of administration: Oral. To be taken three or four times daily.

Adults and children over 12 years: Two to four 5ml spoonfuls.

Children 6–12 years: Two 5ml spoonfuls.

Children 2-6 years: One 5ml spoonful.

Children under 2 years: On medical advice only.

4.3 Contraindications

None known.

4.4 Special Warnings And Precautions For Use

None.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

May be used.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Some gastrointestinal discomfort has been reported.

4.9 Overdose

Very large doses may cause nausea and vomiting. The drug is, however, rapidly metabolised and excreted in the urine. Treatment: The patient should be kept under observation and treated symptomatically.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Guaifenesin is an expectorant. The sugar, honey and glycerin have a demulcent effect.

5.2 Pharmacokinetic Properties

Guaifenesin is absorbed from the gastrointestinal tract. It is metabolised and excreted in the urine.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Purified Honey BP; Sunset Yellow E110; Sucrose, Granular BP; Glycerin BP; Tolu Flavour Solution–Sugar Free HSE; Sodium Benzoate BP; Citric Acid Monohydrate BP; Lemon Oil Terpeneless BP; Isopropyl Alcohol BP; Sodium Cyclamate Ph Eur; Purified Water USP.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store below 20oC.

6.5 Nature And Contents Of Container

Amber glass sirop bottles fitted with a tamper evident cap with fitted polycone liner packed in an outer carton containing 100ml of product.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Cupal Ltd. Venus, 1 Old Park Lane, Trafford Park, Manchester M41 7HA

8. Marketing Authorisation Number(S)

PL 0338/0064.

9. Date Of First Authorisation/Renewal Of The Authorisation

17th November 1987 /26th February 2004.

10. Date Of Revision Of The Text

August 2006


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Boots Pharmacy Anaesthetic Throat Spray


Boots Pharmacy Anaesthetic Throat Spray

(Lidocaine Hydrochloride)

Specifically to:

Relieve severe sore throat pain

20 ml e

Read all of this carton for full instructions.

A local anaesthetic spray to provide direct and soothing relief from the pain of severe sore throats.

Before you use this medicine Do not use: If you are allergic to any of the ingredients If you have asthma, or difficulty breathing If you are under 12 years of age Talk to your pharmacist or doctor: If you are receiving any medical treatment If you have a high fever, headache, feel sick or are being sick as well as having a sore throat If you are pregnant or breastfeeding

This spray may cause your tongue to become numb. You must take care when eating or drinking hot foods or drinks.

How to use this medicine

Use at the back of the throat only.

Do not breathe in when you use the spray, or get the spray in your eyes.

To spray: Swing the nozzle through 90° and press.

Before first use or after storing the spray for a long time: Press the spray 3 times away from the face into a sink.

Adults and children of 12 years and over
Three sprays at the back of the throat every 3 hours, if you need to.
Don’t use more than 6 times in any 24 hours.

Do not use for children under 12 years.

Do not use more than the amount recommended above.

If you use too much:

Talk to a doctor straight away. Take your medicine with you.

If symptoms do not go away, talk to your doctor.

Possible side effects

Most people will not have problems, but some may get some.

If you get any of these serious side effects, stop using the spray.

See a doctor at once:

Difficulty in breathing, swelling of the face, neck, tongue or throat (severe allergic reactions)

If you notice any side effect not listed here, please tell your pharmacist or doctor.

Keep all medicines out of the sight and reach of children.

Use by the date on the side of the carton.

Active ingredient

This liquid contains Lidocaine Hydrochloride 2% w/v.

Also contains: purified water, ethanol (30 vol %), sorbitol (E420), sodium citrate, saccharin, quinoline yellow (E104), patent blue V (E131), flavours (peppermint, levomenthol, aniseed).

PL00014/0430

P

Text prepared 10/07

Manufactured for the Marketing Authorisation holder Boots Pharmacy Nottingham NG2 3AA

by

The Boots Company PLC Nottingham NG2 3AA

Contains approximately 150 sprays.

If you need more advice ask your pharmacist.

BTC22021 vE 15/05/08


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Boots Epsom Salts B.P.


1. Name Of The Medicinal Product

Epsom Salts (Magnesium Sulphate BP)

Boots Epsom Salts B.P.

2. Qualitative And Quantitative Composition

Magnesium Sulphate 100%

3. Pharmaceutical Form

Powder for oral solution

4. Clinical Particulars 4.1 Therapeutic Indications

For the symptomatic relief of occasional constipation.

4.2 Posology And Method Of Administration

Adults and children over 12 years: 1 to 4g to be taken in warm water, once daily.

Children under 12 years. Not recommended.

4.3 Contraindications

Intestinal obstruction.

4.4 Special Warnings And Precautions For Use

To be used with caution in elderly or debilitated patients and in those with renal insufficiency.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

This product may interact with tetracyclines, digoxin, vitamins and iron and may potentiate tubocurarine during anaesthesia.

4.6 Pregnancy And Lactation

The use of magnesium containing salts in the first trimester of pregnancy should be avoided.

They should only be used after medical advice if the benefits exceed potentially unknown risks of foetal exposure to magnesium. No adverse effects are anticipated in breast fed infants.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Prolonged excessive use of this product may cause alkalosis and hypermagnesaemia.

4.9 Overdose

Excessive amounts of this medicine may cause diarrhoea and dehydration. Hypermagnesaemia and hypercalcaemia may also occur, particularly if there is impaired renal function. Treatment consists of supportive and symptomatic measures with appropriate correction of fluid and electrolyte balance.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Not applicable.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

Never undertaken by Abdine Limited. This product was granted a 'Licence as of Right' some 25 years ago.

6. Pharmaceutical Particulars 6.1 List Of Excipients

None.

6.2 Incompatibilities

None are recognised.

6.3 Shelf Life

As packaged for sale: Three years

As reconstituted for use: One day

After first opening the container: One month

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

A spirally wound, varnished, cardboard tub with a press-fit lid or polypropylene jar and cap containing 100g, 150g, 200g, 250g, 300g or 500g.

6.6 Special Precautions For Disposal And Other Handling

Take from 1 to 4g in warm water.

7. Marketing Authorisation Holder

Bell Sons & Co (Druggists) Ltd

Gifford House

Slaidburn Crescent

Southport

Merseyside PR9 9AL

8. Marketing Authorisation Number(S)

PL 03105/0068

9. Date Of First Authorisation/Renewal Of The Authorisation

12 February 1999

10. Date Of Revision Of The Text

29th November 2010

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)


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Adult Meltus for Chesty Coughs and Catarrh


1. Name Of The Medicinal Product

Adult Meltus for Chesty Coughs and Catarrh.

2. Qualitative And Quantitative Composition

Guaifenesin 100mg / 5ml

Cetylpyridinium Chloride 2.5mg / 5ml

Sucrose 1.75g / 5ml

Purified Honey 0.5g / 5ml

3. Pharmaceutical Form

Oral liquid

4. Clinical Particulars 4.1 Therapeutic Indications

For the symptomatic relief of coughs and catarrh associated with influenza, colds and mild throat infections.

4.2 Posology And Method Of Administration

Oral.

Adults and children over 12 years:

One or two 5ml spoonfuls to be taken and swallowed slowly every three or four hours. Not recommended for children under 12 years.

4.3 Contraindications

No known contraindications.

4.4 Special Warnings And Precautions For Use

Not suitable for children under 12 years.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Can cause transient abnormality in platelet aggregation patterns determined one hour after ingestion.

4.6 Pregnancy And Lactation

No known contraindications.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Some gastrointestinal discomfort. Very large doses may cause nausea and vomiting.

4.9 Overdose

Very large doses may cause nausea and vomiting, it is however rapidly metabolised and excreted in the urine. The patient should be kept under observation and treated symptomatically.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

A cough linctus containing an expectorant and an oral antiseptic in a honey and syrup demulcent base. The expectorant, guaifenesin, is employed to produce a thinning of mucous secretions and thus gives relief in bronchial catarrh. The antiseptic, cetylpyridinium chloride, is used for the treatment of superficial mouth and throat infections.

5.2 Pharmacokinetic Properties

None stated.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Glycerin

Alcohol (96%)

Aniseed oil

Menthol crystals

Chloroform

Caramel (E150)

Glucose Liquid

Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf Life

Five years.

6.4 Special Precautions For Storage

Store below 25oC.

6.5 Nature And Contents Of Container

Glass amber sirop bottle with tamper evident cap with fitted ploycone liner in an individual carton containing 100ml or 200 ml of product, including a 5ml CE marked polystyrene measuring spoon.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Cupal Limited, Venus, 1 Old Park Lane, Trafford Park, Manchester, M41 7HA

8. Marketing Authorisation Number(S)

PL 0338/5026R

9. Date Of First Authorisation/Renewal Of The Authorisation

14/09/90 / 07/09/99

10. Date Of Revision Of The Text

July 2006


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Boots Heartburn Relief Aniseed Flavour (150ml)


Boots Heartburn Relief Aniseed Flavour

(Calcium Carbonate, Sodium Alginate, Sodium Bicarbonate)

For fast, effective relief of Heartburn and Acid Indigestion Sugar Free

e 150 ml

Read all of this label for full instructions.

Uses: This medicine contains an antacid to relieve the symptoms of indigestion and heartburn in pregnancy and other conditions which cause acid reflux.

Before you take this medicine Do not take: If you are allergic to any of the ingredients Talk to your pharmacist or doctor: If you are on a low salt (sodium) diet (each 5 ml spoonful contains 71 mg of sodium) If you take other medicines ACE inhibitors (for high blood pressure) Quinidine (for heart problems) Medicines to treat infections or malaria Lithium (for mood disorders) Antipsychotics (for mental health conditions) Medicines for epilepsy Medicines for osteoporosis, pain or rheumatoid arthritis

Do not take this medicine within 1 to 2 hours of taking any other medicine.

E214 and E216 may cause allergic reactions such as skin rash (possibly delayed).

How to take this medicine

Shake the bottle well before use.

Adults and children of 12 years and over: Two to four 5 ml spoonfuls.

Children of 6 to 11 years: One to two 5 ml spoonfuls. Swallow this medicine after meals and at bedtime.

Do not give to children under 6 years.

Do not take more than the amount recommended.

If symptoms do not go away within 2 weeks talk to your doctor.

If you take too much: You may get a bloated stomach. If this happens talk to your pharmacist or doctor.

Possible side effects

Most people will not have problems, but some may get some of these:

Constipation, wind, stomach cramps, burping

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

Do not store above 25°C. Do not refrigerate.

Keep all medicines out of the sight and reach of children.

Active ingredients: Each 5 ml of oral suspension contains Calcium Carbonate 80 mg, Sodium Alginate 250 mg, Sodium Bicarbonate 133.5 mg. Also contains: carbomer, sodium hydroxide, saccharin sodium, ethyl hydroxybenzoate (E214), propyl hydroxybenzoate (E216), butyl hydroxybenzoate, isopropyl alcohol, erythrosine (E127), aniseed oil, purified water.

PL04917/0021

Text prepared 11/08

Manufactured for The Boots Company PLC Nottingham NG2 3AA by the Marketing Authorisation holder Pinewood Laboratories Limited Ballymacarbry Clonmel Co. Tipperary Ireland

3581aeMC


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Meggezones


1. Name Of The Medicinal Product

Meggezones

2. Qualitative And Quantitative Composition

Each pastille contains menthol 16.0mg BP

3. Pharmaceutical Form

Pastille.

4. Clinical Particulars 4.1 Therapeutic Indications

Symptomatic relief of sore throats, coughs, colds, catarrh and nasal congestion.

4.2 Posology And Method Of Administration

Allow one pastille to dissolve slowly in the mouth as required.

Maximum daily dose : Adults - 15 pastilles; children aged 6 to 12 years - 10 pastilles; children aged under 6 years - 5 pastilles.

4.3 Contraindications

None known.

4.4 Special Warnings And Precautions For Use

Hypersensitivity to the product is a possible side effect. Contact dermatitis may occur with menthol products.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Safety in pregnancy and lactation has not been established. However menthol-containing products have been used for many years with no ill effect.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

None stated.

4.9 Overdose

Systemic effects due to overdosage are most unlikely.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Menthol in pastille formulation relieves catarrh and other symptoms associated with colds.

5.2 Pharmacokinetic Properties

Menthol is excreted in the urine and bile as a glucuronide.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Modified starch, antifoam 1510, sucrose, liquorice extract powder, liquid glucose (80%) solid (1963); peppermint oil; benzoin; water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Once opened keep in a cool dry place.

6.5 Nature And Contents Of Container

PVC blister packs with aluminium seal in a cardboard box. Packs contain 3, 8, 24, 36 or 48 pastilles.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Schering-Plough Ltd

Shire Park

Welwyn Garden City

Hertfordshire

AL7 1TW

UK

8. Marketing Authorisation Number(S)

PL 0201/0104

9. Date Of First Authorisation/Renewal Of The Authorisation

5 May 1988 / 5 May 1993

10. Date Of Revision Of The Text

November 1998

11. Legal Status

GSL

Meggezones/UK/02-10/1


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Boots Heartburn Relief Aniseed Flavour (500ml)


Boots Heartburn Relief Aniseed Flavour

(Calcium Carbonate, Sodium Alginate, Sodium Bicarbonate)

For fast, effective relief of Heartburn and Acid Indigestion Sugar Free

e 500 ml

Read all of this label for full instructions.

Uses: This medicine contains an antacid to relieve the symptoms of indigestion and heartburn. It can be used for the relief of heartburn in pregnancy, and other conditions, which cause acid reflux.

Before you take this medicine Do not take: If you are allergic to any of the ingredients Talk to your pharmacist or doctor: If you are on a low salt (sodium) diet (each 5 ml spoonful contains 71 mg of sodium, which may be harmful to you) If you take other medicines ACE inhibitors (for high blood pressure) Quinidine (for heart problems) Medicines to treat infections or malaria Lithium (for mood disorders) Antipsychotics (for mental health conditions) Medicines for epilepsy Medicines for osteoporosis, pain or rheumatoid arthritis

Do not take this medicine within 1 to 2 hours of taking any other medicine.

Information about some of the ingredients: This medicine contains E214 and E216 which may cause allergic reactions such as skin rash (possibly delayed).

How to take this medicine

Check the cap seal is not broken before first use. If it is, do not take the medicine.

Shake the bottle well before use.

Adults and children of 12 years and over: Two to four 5 ml spoonfuls.
Children of 6 to 11 years: One or two 5 ml spoonfuls.
Swallow the medicine after meals and at bedtime.

Do not give to children under 6 years.

Do not take more than the amount recommended.

If symptoms do not go away within 2 weeks talk to your doctor.

If you take too much: You may get a bloated stomach. If this happens talk to your pharmacist or doctor.

Possible side effects

Most people will not have problems, but some may get some of these:

Constipation, wind, stomach cramps, burping

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

How to store this medicine

Do not store above 25°C.

Do not refrigerate.

Keep all medicines out of the sight and reach of children.

Use by the date on the label edge.

Active ingredients

Each 5 ml of oral suspension contains Calcium Carbonate 80 mg, Sodium Alginate 250 mg, Sodium Bicarbonate 133.5 mg.

Also contains: carbomer, sodium hydroxide, saccharin sodium, ethyl hydroxybenzoate (E214), propyl hydroxybenzoate (E216), butyl hydroxybenzoate, isopropyl alcohol, erythrosine (E127), aniseed oil, purified water.

PL04917/0021

Text prepared 11/08

Manufactured for The Boots Company PLC Nottingham NG2 3AA by the Marketing Authorisation holder Pinewood Laboratories Limited Ballymacarbry Clonmel Co. Tipperary Ireland

If you need more advice ask your pharmacist

3581eMC


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Chloraseptic Sore Throat Spray


phenol
Dosage Form: oral spray
Chloraseptic Sore Throat Grape Spray

Drug Facts

Active ingredient

Phenol 0.5%

Purpose

Oral Anesthetic/Analgesic

Uses

For the temporary relief of occasional minor irritation, pain, sore mouth and sore throat.

Warnings

Sore Throat Warning: Severe or persistent sore throat or sore throat accompanied by high fever, headache, nausea, and vomiting may be serious. Consult doctor promptly. Do not use more than 2 days or administer to children under 3 years of age unless directed by a doctor.


When using this product

do not exceed recommended dosage.

Stop use and ask a doctor or dentist if sore mouth symptoms do not improve in 7 days
irritation, pain or redness persists or worsens
swelling, rash or fever develops

If pregnant or breast-feeding, ask a health care professional before use.

Keep out of reach of children.

In case of overdose or accidental poisoning, get medical help or contact a Poison Control Center right away.

Directions

Adults and children 3 years of age and older:

Apply to the affected area (one spray).
Allow to remain in place for at least 15 seconds, then spit out.
Use every 2 hours or as directed by a doctor or dentist. Children under 12 years of age should be supervised in the use of this product. Children under 3 years of age: consult a doctor or dentist. Other information Store at room temperature.
Tamper Evident: Do not use if imprinted shrink band is broken or missing.
Check expiration date before using. Inactive ingredients

FD&C Blue #1, FD&C Red #40, flavor, glycerin, purified water, sodium saccharin, sodium chloride

Questions?

1-800-552-7932 www.chloraseptic.com

PRINCIPAL DISPLAY PANEL

Kids Chloraseptic® Phenol/Oral Anesthetic
SORE THROAT
Real Relief, Real Fast®
GRAPE | 6 fl oz (177 mL)


CHLORASEPTIC SORE THROAT 
phenol  spray Product Information Product Type HUMAN OTC DRUG NDC Product Code (Source) 67172-935 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PHENOL (PHENOL) PHENOL 3.5 mg  in 0.7 mL Inactive Ingredients Ingredient Name Strength FD&C BLUE NO. 1   FD&C RED NO. 40   WATER   GLYCERIN   SODIUM CHLORIDE   Product Characteristics Color PURPLE Score      Shape Size Flavor GRAPE Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 67172-935-51 177 mL In 1 BOTTLE, SPRAY None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date OTC MONOGRAPH FINAL part348 09/01/2010
Labeler - Prestige Brands Holdings, Inc. (159655021) Establishment Name Address ID/FEI Operations Accupac, Inc. 071609663 MANUFACTURE Revised: 10/2010Prestige Brands Holdings, Inc.
More Chloraseptic Sore Throat Spray resources Chloraseptic Sore Throat Spray Use in Pregnancy & Breastfeeding 1 Review for Chloraseptic Sore Throat - Add your own review/rating Compare Chloraseptic Sore Throat Spray with other medications Tonsillitis/Pharyngitis
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Boots Easy Breathing Pastilles


1. Name Of The Medicinal Product

Boots Easy Breathing Pastilles

2. Qualitative And Quantitative Composition

Sylvestris Pine Oil

0.3% V/W

Abietis Oil BPC 1949

0.3% V/W

Menthol BP

0.6% W/W

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Pastille

4. Clinical Particulars 4.1 Therapeutic Indications

For the relief of catarrhal symptoms and coughs

4.2 Posology And Method Of Administration

One pastille to be dissolved slowly in the mouth as required.

ADULTS, THE ELDERLY AND CHILDREN OF 12 YEARS AND OVER:

Do not take more than 18 pastilles in 24 hours.

CHILDREN 6 – 12 YEARS:

Do not take more than 12 pastilles in 24 hours.

Not recommended for children under 6 years old.

4.3 Contraindications

Hypersensitivity to any of the ingredients

4.4 Special Warnings And Precautions For Use

Keep out of reach and sight of children. If symptoms persist consult your doctor.

Contains a total of 1.3g of sucrose and glucose per pastille. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None reported

4.6 Pregnancy And Lactation

The use of Catarrh Pastilles during pregnancy and lactation is not restricted.

4.7 Effects On Ability To Drive And Use Machines

None

4.8 Undesirable Effects

Isolated cases of hypersensitivity reactions including anaphylaxis, angioedema, bronchospasm, rash, urticaria and flushing have been reported with menthol-containing preparations.

4.9 Overdose

No example of overdose has been reported.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

All the actives have decongestant properties.

5.2 Pharmacokinetic Properties

Not applicable

5.3 Preclinical Safety Data

There is no preclinical data available specific to the product.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Granulated sugar

Modified starch

Liquid Glucose BPC

Peppermint oil

Eucalyptus oil

Water

6.2 Incompatibilities

None known

6.3 Shelf Life

60 months for the unopened pack.

3 months after opening the 45g pack.

6 months after opening the 500g pack.

6.4 Special Precautions For Storage

None

6.5 Nature And Contents Of Container

Tied polythene bag, 500 g

Securitainer, 500 g

Heat-sealed laminated sachet integral with carton, 45 g

6.6 Special Precautions For Disposal And Other Handling

None specific to the packs.

7. Marketing Authorisation Holder

Ernest Jackson & Co Ltd

High Street

Crediton

Devon, EX17 3AP, UK

8. Marketing Authorisation Number(S)

PL 0094/5014R

9. Date Of First Authorisation/Renewal Of The Authorisation

First granted 23 April 1987 / Renewed June 2004

10. Date Of Revision Of The Text

July 2011


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Glycerin Honey and Lemon Linctus with Ipecacuanha / Boots Sore Throat and Cough Linctus 2 Years Plus


1. Name Of The Medicinal Product

Glycerin Honey and Lemon Linctus with Ipecacuanha or Boots Sore Throat & Cough Linctus 2 Years +

2. Qualitative And Quantitative Composition

Active Ingredient

Per 5ml

 

Honey mfg

1.11g

Glycerin Ph Eur

0.75ml

Liquid Sugar Demin

2.2ml

Ipecacuanha Liquid Extract

0.015ml

3. Pharmaceutical Form

Linctus

4. Clinical Particulars 4.1 Therapeutic Indications

For the relief of coughs and sore throats.

For oral administration.

4.2 Posology And Method Of Administration

Adults and children over 12 years: 10ml

Children 6 to 12 years: 5ml

Children 2 to 5 years: 2.5ml

This dose may be taken up to three or four times a day if needed.

Not more than 4 doses should be given in any 24 hours. Do not exceed the stated dose.

Elderly: There is no need for dosage reduction in the elderly.

4.3 Contraindications

Hypersensitivity or intolerance to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Consult a pharmacist or other healthcare professional before use in children under 6 years.

Do not give with any other cough and cold medicine.

If symptoms persist consult your doctor.

Keep all medicines out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant drug interactions known.

4.6 Pregnancy And Lactation

The safety of this product during pregnancy and lactation has not been established, and its use during these periods should be avoided.

4.7 Effects On Ability To Drive And Use Machines

No known adverse effects.

4.8 Undesirable Effects

No adverse effects would be anticipated.

4.9 Overdose

Overdosage may have an irritant effect on the gastrointestinal tract and persistent bloody vomiting or diarrhoea may occur. In severe cases may give rise to adverse effects on the heart such as conduction abnormalities or myocardial infarction. These combined with dehydration due to vomiting and diarrhoea, may cause circulatory collapse.

Initial treatment of severe overdosage involves the administration of activated charcoal to delay absorption, followed by gastric lavage. Prolonged vomiting may be controlled by intramuscular injection of antiemetics. Fluid and electrolyte balance should be corrected, as should any cardiac defects.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Glycerin, syrup and honey have demulcent properties and will soothe irritated sore throats.

Ipecacuanha has expectorant properties.

5.2 Pharmacokinetic Properties

Glycerol is readily absorbed from the gastrointestinal tract and undergoes extensive metabolism principally in the liver. It may be used in the synthesis of lipids, and is metabolised to glucose or glycogen or oxidised to carbon dioxide and water. It may also be excreted in the urine unchanged.

Sucrose is hydrolysed in the small intestine by the enzyme sucrase to glucose and fructose which are then absorbed.

No detailed pharmacokinetic data is available for Ipecacuanha.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lemon oil

Citric acid monohydrate

Terpeneless lemon oil

Benzoic acid

Distilled lime oil

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

A white flint glass bottle with an unlined or LDPE/EPE/LDPE lined polypropylene cap.

Alternative cap: A roll-on pilfer-proof cap with a flowed-in liner or a triseal (LDPE/EPE/LDPE) liner.

Pack size: 100, 125, 200 ml

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

8. Marketing Authorisation Number(S)

PL00014/5152R

9. Date Of First Authorisation/Renewal Of The Authorisation

First Authorisation: 8 February 1989

Date of Last Renewal: 12 July 1999

10. Date Of Revision Of The Text

March 2008


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Diocalm


1. Name Of The Medicinal Product

Diocalm Tablets

2. Qualitative And Quantitative Composition

Morphine Hydrochloride 0.395mg

Activated Attapulgite 312.5mg

Attapulgite 187.5mg

For excipients, see 6.1.

3. Pharmaceutical Form

Tablet.

4. Clinical Particulars 4.1 Therapeutic Indications

For the relief of occasional diarrhoea and its associated pain and discomfort.

4.2 Posology And Method Of Administration

Directions for use:

The tablets should be chewed and then followed by a drink of water. As well as using Diocalm, it is important to replace body fluids lost during diarrhoea.

Recommended dose:

Adults and children aged 12 years and over: 2 tablets.

Children aged 6 to under 12 years: 1 tablet.

The recommended dose should be taken every two to four hours as required according to the severity of the symptoms.

Do not take more than six doses in 24 hours.

Not to be given to children under 6 years.

Elderly: as the adult dose.

4.3 Contraindications

Patients with impaired renal function.

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Labelling:

Warning: Do not exceed the stated dose.

Keep out of reach of children.

If symptoms persist for more than 24 hours, consult your doctor.

As well as taking Diocalm, it is important to replace body fluids lost during diarrhoea.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None.

4.6 Pregnancy And Lactation

There are no known contraindications to the use of the product during pregnancy and lactation, but as with all medicines caution should be exercised.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

None.

4.9 Overdose

Overdosage is considered a theoretical possibility but, in practice, not a significant hazard with the small level of morphine in the product (40 tablets contain 15.8mg of morphine hydrochloride, an analgesic dose). Larger doses would cause nausea, vomiting, constipation, drowsiness and confusion. Convulsions may occur in infants and children. Morphine dependence is not considered to be a likely problem with the low doses of morphine present in the product.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Morphine, combinations, ATC code: A07DA52

Morphine acts by antimotility and antisecretory mechanisms on the gastrointestinal tract and is used in the symptomatic treatment of diarrhoea.

Attapulgite and activated attapulgite are effective gastrointestinal adsorbents.

5.2 Pharmacokinetic Properties

Morphine salts are absorbed from the gastrointestinal tract. Conjugation to morphine 3- and 6-glucoronides occurs in the liver. About 10% of a dose of morphine is excreted through the bile into the faeces and the remainder is excreted in the urine, mainly as conjugates.

Attapulgite and activated attapulgite have a local action in the gastrointestinal tract. They are insoluble and remain unabsorbed.

5.3 Preclinical Safety Data

Preclinical safety data on these active ingredients in the literature have not revealed any pertinent and conclusive findings which are of relevance to the recommended dosage and use of the product.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Icing Sugar

Paregoric Essence

Magnesium Stearate.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Blister strips made of PVC/PVDC coated plastic with aluminium foil backing. Each strip contains 10 tablets. Two or four strips are contained in a boxboard carton.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

SSL International PLC. Venus, 1 Old Park Lane, Trafford Park, Manchester, M41 7HA.

8. Marketing Authorisation Number(S)

PL 17905/0048

9. Date Of First Authorisation/Renewal Of The Authorisation

31/01/06

10. Date Of Revision Of The Text

23/01/07


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Boots Bite & Sting Relief Liquid


Boots Bite and Sting Relief Liquid

(Ammonia)

Fast relief from insect bites and stings

mosquitoes, horse flies, wasps, bees, nettles, jelly fish

14 ml

topical emulsion

Read all of this carton for full instructions.

Uses: For the relief of itching from insect bites, including mosquitoes and horse flies, and the relief of stinging from wasps, bees, jelly fish and nettles.

Before you use this medicine Do not use: If you are allergic to any of the ingredients

You can use this medicine if you are pregnant or breastfeeding.

How to use this medicine

Shake the bottle well before use.

Adults and children of 2 years and over: Rub the applicator directly onto the bite or sting, when you need to. Repeat if the itching does not go away. It is better to use this medicine as soon as possible after you are bitten or stung. Do not bandage or cover the affected area until the liquid is dry.

Apply to the skin only.

Avoid contact with the mouth and eyes. If this happens rinse well with water.

Do not use on children under 2 years.

If symptoms do not go away talk to your doctor.

If anyone accidentally swallows some: Drink milk and citrus juices and talk to a doctor straight away. Take your medicine with you.

Possible side effects

This medicine is not expected to cause side effects.

However, if any of the following effects continue or worsen stop using the medicine and see a doctor:

Rash, redness, irritation, pain, swelling

If you notice any other side effect, please tell your pharmacist or doctor.

How to store this medicine

Do not store above 25°C.

Keep all medicines out of the sight and reach of children.

Use by the date on the bottom of the carton.

Active ingredient

This liquid contains Ammonia 3.5% w/v.

Also contains: mineral oil, alcohol ethoxylate, dimeticone, purified water.

PL 15536/0001

Text prepared 1/09

Manufactured for

The Boots Company PLC Nottingham NG2 3AA

by

Ardern Healthcare Ltd Tenbury Wells WR15 8NP

Marketing Authorisation held by

Tender Limited Netqubate Business Centre 72-73 Bartholemew Street Newbury Berkshire RG14 5DU

If you need more advice ask your pharmacist.


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Wind-Eze Tablets


1. Name Of The Medicinal Product

Wind-Eze

2. Qualitative And Quantitative Composition

Simeticone [Equivalent to Poly(Dimethylsiloxane)], 11.57% w/w, approx. 125.00mg

3. Pharmaceutical Form

Chewable tablets for oral administration.

4. Clinical Particulars 4.1 Therapeutic Indications

Antiflatulent defoaming agent for the symptomatic relief of flatulence, wind pains, bloating, abdominal distension and other similar symptoms associated with gastrointestinal gas.

4.2 Posology And Method Of Administration

Adults, elderly and children over 12 years:

One tablet to be taken three or four times daily or as required for relief, after meals and upon retiring. The tablets are to be chewed before swallowing.

Not recommended for children under 12 years.

4.3 Contraindications

The product should not be used in patients with known hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

If symptoms persist or worsen, medical advice should be sought.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Since simeticone is not absorbed by the gastro intestinal tract, Wind-Eze may be taken during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Rarely hypersensitivity reactions such as rash, pruritus, facial oedema, tongue oedema, respiratory difficulty.

4.9 Overdose

In the unlikely event of deliberate or accidental overdosage, treat symptoms on appearance. There are no special procedures recommended.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Physiologically simeticone is extremely inert, and therefore it will not be pharmacologically active.

5.2 Pharmacokinetic Properties

Simeticone (activated dimeticone) is not absorbed following oral administration. It acts by changing the surface tension of gas bubbles, causing them to coalesce.

5.3 Preclinical Safety Data

Simeticone is physiologically inert and considered to be non-toxic. It is not absorbed following oral administration, nor is it pharmacologically active. Preclinical data reveal no hazard for humans.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Dextrates (hydrated) USNF

Sorbitol Crystalline EP

Tribasic Calcium Phosphate (Powder) USNF

Citric Acid Anhydrous (Powder) EP

Natural and artificial peppermint flavour No. 517

(Spray dried) HSE

Talc (purified) EP

Non-pareil seeds (Starch/Sucrose) HSE

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years in PVC/PVDC Al foil blister packs. 3 years in PVC/PE/Aclar Al. foil blister packs.

6.4 Special Precautions For Storage

Store below 25oC.

Store in a dry place.

6.5 Nature And Contents Of Container

Blister packs of construction 190 ?m PVC (product contact side)/51?m PE/38?m aclar and 25?m aluminium foil with vinyl sealing coat (product contact side).

or

Blister packs of construction 250?m PVC (product contact side)/PVDC 60 g/m2 and 20 ?m aluminium foil with vinyl heat sealing coat (product contact side).

Pack sizes: 4, 10, 20, 30, 50.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Stafford-Miller Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

Trading as GlaxoSmithKline Consumer Healthcare, Brentford TW8 9GS, U.K.

8. Marketing Authorisation Number(S)

PL 00036/0084

9. Date Of First Authorisation/Renewal Of The Authorisation

25th May 2001

10. Date Of Revision Of The Text

February 2008


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Boots Catarrh Pastilles


Boots Catarrh Pastilles

(Eucalyptus Oil, Menthol, Pumilio Pine Oil)

relieves catarrh, coughs and colds

45 g

Read all of this carton for full instructions.

What this medicine is for

This medicine contains menthol, eucalyptus and pumilio oils, which relieve chesty coughs and have antiseptic properties. It can be used to relieve the symptoms of congestion caused by catarrh, coughs and colds.

Before you take this medicine Do not take: If you are allergic to any of the ingredients If you have an intolerance to some sugars, unless your doctor tells you to (this medicine contains glucose and sucrose) Talk to your pharmacist or doctor: If you are pregnant or breastfeeding

Information about some of the ingredients: Each pastille contains a total of 0.8 g of glucose and sucrose. This should be taken into account by people with diabetes. The colour E122 in this medicine may cause allergic reactions.

How to take this medicine

Check the inner bag is not broken before use. If it is, do not use the pastilles.

Adults and children of 12 years and over: Suck one pastille when you need to.

Don’t take more than 20 pastilles in 24 hours.

Suck each pastille slowly until it dissolves.

Do not give to children under 12 years.

Do not take more than the amount recommended.

If symptoms do not go away, talk to your doctor.

If you take too many pastilles: Talk to a pharmacist or doctor straight away.

Possible side effects

Most people will not have problems, but some may get some.

If you get any of these serious side effects, stop taking the pastilles. See a doctor at once:

Difficulty in breathing, swelling of the face, neck, tongue or throat (severe allergic reactions)

If any side effect becomes severe, or you notice any side effect not listed here, please tell your pharmacist or doctor.

How to store this medicine

Do not store above 25°C.

Keep all medicines out of the sight and reach of children.

Use by the date on the end flap of the carton.

Active ingredients

Each pastille contains Eucalyptus Oil 0.02% v/w, Menthol 0.8% w/w, Pumilio Pine Oil 0.6% v/w.

Also contains: modified starch, sucrose, glucose syrup, marshmallow liquid extract, vegetable oil, beeswax, water, thymol, carmoisine (E122).

PL 00094/0009

Text prepared 8/09

Manufactured for

The Boots Company PLC Nottingham NG2 3AA

by The Marketing Authorisation holder

Ernest Jackson and Co Crediton Devon EX17 3AP

If you need more advice ask your pharmacist.


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Boots Pain Relief Heat Spray


Boots Pain Relief heat spray

(Ethyl Nicotinate 1.1% w/w, Methyl Salicylate 1.25% w/w, Racemic Camphor 0.625% w/w)

Effective relief for muscular and rheumatic pain

125 ml e

Read this can for full instructions.

Uses

A warming pain relieving spray for the relief of muscular and rheumatic pain, lumbago, fibrositis, sciatica, sprains, strains and stiffness. No massage necessary.

Before you use this medicine Do not use: If you are allergic to any of the ingredients If you are pregnant or breastfeeding, unless your doctor agrees On broken or damaged skin, or on open cuts On children under 5 years of age How to use

Keep the spray away from the eyes, face, lining of mouth, throat and nose, and other sensitive areas of the body. Do not inhale the spray.

Apply to the skin only.

Hold the can 6 inches (15 cm) away from the skin.

Adults and children of 5 years and over:

Spray the painful area with 2 or 3 short bursts of spray.

Only use a small amount of spray because using too much can irritate the skin.

If the symptoms do not go away, talk to your doctor.

If you accidentally use too much spray it will not usually cause any problems.

Possible side effects

Most people will not have problems.

If you get any of these stop using the spray. If you notice any side effect not listed here, please tell your pharmacist or doctor. Skin irritation Allergic reaction (such as itching or redness of the skin) Active ingredients

This topical spray contains Ethyl Nicotinate 1.1% w/w, Methyl Salicylate 1.25% w/w, Racemic Camphor 0.625% w/w.

Also contains: denatured ethanol, butane, isobutane, propane.

Keep all medicines out of the sight and reach of children.

Use by the date on base of the can.

PL 00014/0275

Text prepared 3/06

Manufactured for the Marketing Authorisation holder The Boots Company PLC Nottingham NG2 3AA

by

ColepCCL UK Limited Atkinsons Way Foxhills Industrial Park Scunthorpe North Lincolnshire DN15 8QJ

Caution: Pressurised container. Protect from sunlight.

Do not expose to temperatures above 50°C.

Do not pierce or burn even when empty.

Do not use near, or place on painted or polished surfaces.

EXTREMELY FLAMMABLE

125 ml

175

Э

Do not spray on a naked flame or on incandescent material. Keep away from sources of ignition. No smoking.

If you need more advice ask your pharmacist.

BTC19928 vA 24/07/07


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Wasp-Eze Bites and Stings Spray


1. Name Of The Medicinal Product

Wasp-Eze Bites and Stings Spray

2. Qualitative And Quantitative Composition

Benzocaine 1.0% w/w

Mepyramine Maleate 0.5% w/w

For excipients, see 6.1.

3. Pharmaceutical Form

Cutaneous Spray.

A clear uniform spray.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of all insect bites and stings, nettle stings and jellyfish stings in adults and children aged 2 years and over.

4.2 Posology And Method Of Administration

For cutaneous application.

For adults and children aged 2 years and over:

Hold nozzle approximately five inches from the skin and spray once for 2-3 seconds. Stop spraying immediately if a white deposit or “frost” appears. Repeat once after 15 minutes if necessary. If pain persists, seek medical advice.

4.3 Contraindications

Do not use if you are sensitive to any of the ingredients

Do not apply to large areas of skin, eczematous, sunburnt or broken skin.

Do not use the spray on the face.

4.4 Special Warnings And Precautions For Use

Patients with any known allergy to insect bites or stings should seek medical advice. If pain persists, seek medical advice.

Not for repeated or prolonged use.

For external use only. Keep out of the reach and sight of children.

Flammable. Do not use near fire or flame. Pressurised container. Protect from sunlight and do not expose to temperatures exceeding 50oC. Do not pierce or burn, even after use. Do not spray on a naked flame or any incandescent material. Do not use near or place container on polished or painted surfaces.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Not for use in pregnancy or lactation unless on medical advice.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Skin rash.

Methaemoglobinaemia especially in infants and children.

4.9 Overdose

Overdose is unlikely with this dosage form. There are no known effects and no specific treatment.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

The ingredients, benzocaine (D04 AB04) and mepyramine maleate (D04 AA02), reduce pain and histamine responses to stings. The physical effects of the cooling propellants help reduce pain.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Propylene glycol

Ethanol, denatured

Iso-butane

N-pentane

Dimethyl ether

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Do not store above 25oC.

6.5 Nature And Contents Of Container

30 ml Aluminium cans internally coated with epoxyphenolic lacquer fitted with valve assembly and actuator button, protected by a plastic cap.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Seton Products Limited

Tubiton House

Oldham

OL1 3HS

8. Marketing Authorisation Number(S)

PL 11314/0145

9. Date Of First Authorisation/Renewal Of The Authorisation

25th November 2004

10. Date Of Revision Of The Text

January 2005


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FYBOGEL PLAIN


1. Name Of The Medicinal Product

Fybogel.

2. Qualitative And Quantitative Composition

Each single dose sachet contains 3.5g ispaghula husk BP.

3. Pharmaceutical Form

Effervescent granules for preparation of an oral suspension

4. Clinical Particulars 4.1 Therapeutic Indications

The treatment of patients requiring a high fibre regimen: for example, for the relief of constipation including constipation in pregnancy and the maintenance of regularity; for the management of bowel function in patients with colostomy, ileostomy, haemorrhoids, anal fissure, chronic diarrhoea associated with diverticular disease, irritable bowel syndrome and ulcerative colitis.

4.2 Posology And Method Of Administration

Fybogel should be stirred into a glass of water and taken as soon as effervescent subsides, preferably after meals.

Adults and children over 12 years:

One sachet morning and evening.

Elderly:

There is no indication the dosage need be modified for the elderly.

Children 6-12 years:

Half to one level 5ml spoonful depending on size and age morning and evening.

Children under 6 years:

To be taken only when prescribed by a doctor. Half to one level 5ml spoonful depending on size and age morning and evening.

4.3 Contraindications

Fybogel is contra-indicated in cases of intestinal obstruction, faecal impaction and colonic atony such as senile mega-colon.

4.4 Special Warnings And Precautions For Use

Due to its aspartame content, Fybogel should not be given to patients with phenylketonuria.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known

4.6 Pregnancy And Lactation

Fybogel may be used during pregnancy and lactation since the ispaghula husk is not absorbed from the gastrointestinal tract.

4.7 Effects On Ability To Drive And Use Machines

Not applicable in view of physical mode of action.

4.8 Undesirable Effects

None known

4.9 Overdose

In the event of overdosage conservative measures should be taken. The patient may notice abdominal discomfort and flatulence and attention should be paid to maintaining an adequate fluid intake, particularly if the granules have been taken without water, contrary to administration instructions.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Ispaghula husk is capable of absorbing up to 40 times it own weight of water in vitro and part of its activity can be attributed to its action as a simple bulking agent. In addition colonic bacteria are believed to use the hydrated material as a metabolic substrate. This results in an increase in the bacterial cell mass with a consequent softening of the faeces.

5.2 Pharmacokinetic Properties

The mode of action of Fybogel is physical and does not depend on absorption into the systemic circulation.

5.3 Preclinical Safety Data

No preclinical findings relevant to the prescriber have been reported.

6. Pharmaceutical Particulars 6.1 List Of Excipients Potassium bicarbonate USP Sodium bicarbonate Ph Eur Citric acid Ph Eur Riboflavin sodium phosphate Ph Eur Beta-caotene 10 % (E160a) HSE Aspartame Ph Eur Saccharin sodium Ph Eur Polysorbate 80 Ph Eur Silica, colloidal anhydrous Ph Eur 6.2 Incompatibilities

None known

6.3 Shelf Life

Three years

6.4 Special Precautions For Storage

Store below 30°C in a dry place.

6.5 Nature And Contents Of Container

Sachets of paper/aluminium foil/polythene laminate enclosed in a cardboard outer carton.

Pack size(s): Ten or thirty sachets (pack size printed in bold is currently sold).

6.6 Special Precautions For Disposal And Other Handling

No special instructions.

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Limited

Dansom Lane

Hull

HU8 7DS

United Kingdom

8. Marketing Authorisation Number(S)

PL 00063/0023

9. Date Of First Authorisation/Renewal Of The Authorisation

15/01/1990 / 09/06/2003

10. Date Of Revision Of The Text

17/01/2007


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