Petol

Petol is 5H-dibenzo[b,f]azepine-5-carboxamide.

Excipients/Inactive Ingredients: Tablet: Aerosil 200 (silica, colloidal anhydrous), Avicel PH 101 (cellulose) magnesium stearate, Nymcel ZSB-10 modified (carmellose sodium, low substituted).

CR Tablet: Aerosil 200 (silica, colloidal anhydrous), ethylcellulose aqueous dispersion, Avicel PH 102 (cellulose), Eudragit ED solid (copolymer based on polyacrylic/methacrylic esters), magnesium stearate, sodium CMC XL, talc. Coating: Cellulose-HP-M 603 (hydroxypropyl methylcellulose), Cremophor RH 40 (glyceryl polyoxyethylene glycol stearate), iron oxide red, iron oxide yellow, talc, titanium dioxide.

Oral Suspension:

Acute Manic Or Mixed Episodes Associated With Bipolar I Disorder

Petol is indicated for treatment of patients with acute manic or mixed episodes associated with bipolar I disorder.

Pain Of Trigeminal Neuralgia

Petol is indicated in the treatment of the pain associated with 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.

Epilepsy

Petol is indicated for the treatment of partial seizures with complex symptomatology (e.g., psychomotor, temporal lobe), generalized tonic-clonic seizures (grand mal), and mixed seizure patterns, which include the seizure types listed here or other partial or generalized seizures..

Limitations Of Usage

Petol is not indicated for the treatment of absence seizures (petit mal).Petol has been associated with increased frequency of generalized convulsions in these patients.

DOSAGE AND ADMINISTRATION

Pretreatment Screening

Prior to initiating treatment with Petol, test patients with ancestry in genetically at-risk populations for the presence of the HLA-B*1502 allele. The high resolution genotype test is positive if one or two HLA-B*1502 alleles are present. Avoid use of Petol in patients testing positive for the allele, unless the benefit clearly outweighs the risk.

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 Petol 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 Petol because liver damage may occur. Discontinue Petol in cases of aggravated liver dysfunction or 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.

Dosage For Acute Manic Or Mixed Episodes Associated With Bipolar I Disorder

The recommended initial dose of Petol is 200 mg administered twice daily. The dose may be increased by 200 mg per day to achieve optimal clinical response. Doses higher than 1600 mg per day have not been studied in mania associated with bipolar disorder.

Dosage For Pain Of Trigeminal Neuralgia

Initial: On the first day, start with one 200 mg capsule once daily. This dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours only as needed to reach an effective and tolerated dose. Do not exceed a total daily dose of 1200 mg.

Maintenance: Control of pain can be maintained in most patients with 400 mg to 800 mg daily. However, some patients may be maintained on as little as 200 mg daily, while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period, attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug.

Dosage For Epilepsy

Adults And Children Over 12 Years Of Age

The recommended initial dose is 200 mg administered twice daily. Increase in weekly increments of 200 mg a day, administered as an equally divided, twice daily dose, until an optimal response is obtained. Dosage generally should not exceed 500 mg twice daily in children 12 to 15 years old; 600 mg twice daily in children 15 to 18 years old; and 800 mg twice daily in adults.

Children Under 12 Years Of Age

Ordinarily, optimal clinical response is achieved at daily doses below 35 mg/kg. No recommendation regarding the safety of Petol for use at doses above 35 mg/kg/24 hours can be made.

Co-Administration With Other AEDs

Petol may be used alone or with other AEDs. When added to existing AEDs, add Petol gradually while the dosage(s) of other AEDs are maintained or gradually decreased. Potential drug interactions should be considered when using Petol with other AEDs.

Switching From Immediate-Release Petol To Petol

Petol is an extended-release formulation for twice a day administration. When converting patients from immediate release Petol to Petol extended-release capsules, the same total daily mg dose of Petol should be administered. Following conversion to Petol, patients should be closely monitored for seizure control. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions.

Discontinuation Of Petol

When discontinuing Petol used for any indication, reduce the dose gradually and avoid abrupt discontinuation in order to decrease the risk of seizure.

Monitoring Serum Petol Concentration

Monitoring serum Petol concentrations may be useful for dose selection, minimizing toxicity, and verifying drug compliance, especially in clinical conditions in which alterations in Petol metabolism can occur (e.g., drug interactions). In pediatric patients treated with Petol for epilepsy, if satisfactory clinical response has not been achieved, measure plasma levels to determine whether or not they are in the therapeutic range.

Administration Instructions

Swallow Petol capsules whole or open and sprinkle the beads over food, such as a teaspoon of applesauce. Do not crush or chew Petol capsules or the beads inside the capsule. Petol can be taken with or without meals.

Petol is used to treat certain types of seizures (epilepsy). It is also used to relieve pain due to trigeminal neuralgia (tic douloureux) and in the treatment of bipolar disorder (manic-depressive illness). Petol works in the brain and nervous system to control seizures, pain, and bipolar disorder. Petol is an anticonvulsant.

Petol is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, Petol is used in certain patients with the following medical conditions:

• Alcohol withdrawal.
• Bipolar disorder (manic-depressive illness), prevention.
• Central partial diabetes insipidus (water diabetes).
• Neurogenic pain (a type of continuing pain).
• Psychotic disorders (severe mental illness).

Dosage Information

Petol is a replacement therapy for oral Petol. Petol treatment should generally be initiated with an oral Petol formulation.

The total daily dose of Petol is 70% of the total daily oral Petol dose from which patients are being switched. The total daily dose of Petol should be equally divided in four 30-minute infusions, separated by 6 hours.

Patients should be switched back to oral Petol administration at their previous total daily oral dose and frequency of administration as soon as clinically appropriate. The use of Petol for periods of more than 7 days has not been studied.

Table 1. Determination of Total Daily Dose for Petol Infusion

Administration Information

Petol is for intravenous use only and must be diluted in a compatible diluent prior to infusion.

Using Table 2 as a guide, prepare the solution for each infusion by transferring the single dose volume of Petol to 100 mL of diluent solution (0.9% sodium chloride, lactated Ringer’s solution, or 5% dextrose) and mixing gently.

Before administration, the prepared solution for infusion may be stored for a maximum of 4 hours at 20°C to 25°C (68°F to 77°F) or a maximum of 24 hours if refrigerated at 2°C to 8°C (36°F to 46°F).

Parenteral drug products should be inspected visually for particulate matter, cloudiness, or discoloration prior to administration, whenever solution and container permit. If any of these are present, discard the solution.

Administer each infusion intravenously over 30 minutes.

Petol injection vials are for single-dose only. Discard any unused portion.

Table 2. Petol Dose to Volume and Infusion Table

Renal Function Monitoring

Patients with renal impairment may be at greater risk for an adverse effect of Petol on renal function, and should have close monitoring of renal function during treatment with Petol. Petol should generally not be used in patients with moderate or severe renal impairment.

Serum Level Monitoring

Monitor serum Petol concentrations in conditions in which alterations in Petol metabolism can occur. This includes patients who have hepatic impairment and patients on drugs that either induce or inhibit Petol metabolism.

Laboratory Testing Prior To Petol Initiation

Prior to initial treatment with Petol, test patients with ancestry in genetically at-risk populations for the presence of the HLA-B*1502 allele. The high resolution genotype test is positive if one or two HLA-B*1502 alleles are present. Avoid use of Petol in patients testing positive for the allele, unless the benefit clearly outweighs the risk.

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 Petol 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 Petol because liver damage may occur. Discontinue Petol in cases of aggravated liver dysfunction or active liver disease.

How supplied

Dosage Forms And Strengths

Petol injection contains 200 mg/20 mL (10 mg/mL) Petol as a clear, colorless, sterile solution in a single-dose vial.

Storage And Handling

Petol (Petol) 200 mg/20 mL (10 mg/mL) injection is a clear, colorless, sterile solution. It is supplied in single-dose 20 mL glass vials, available in cartons of one vial (NDC 67386-621-52). Not made with natural rubber latex.

Storage And Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Manufactured by: Baxter Pharmaceuticals Solutions, LLC, Bloomington, IN 47403, U.S.A. Revised: October 2016

See also:
What is the most important information I should know about Petol?

You should not take Petol if you have a history of bone marrow suppression, if you are also taking nefazodone, or if you are allergic to an antidepressant such as amitriptyline, desipramine, imipramine, or nortriptyline.

This medication may cause severe or life-threatening skin rash. Your doctor may recommend a blood test before you start the medication to determine your risk.

Do not start or stop taking Petol during pregnancy without your doctor's advice. Petol may cause harm to an unborn baby, but having a seizure during pregnancy could harm both the mother and the baby. Tell your doctor right away if you become pregnant while taking Petol for seizures.

TELL YOUR DOCTOR ABOUT ALL OTHER MEDICINES YOU USE. Some drugs can raise or lower your blood levels of Petol, which may cause side effects or make Petol less effective. Petol can also affect blood levels of certain other drugs, making them less effective or increasing side effects.

Use Petol suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Petol suspension comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Petol suspension refilled.
• Take Petol suspension by mouth with food.
• Shake well before each use.
• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.
• If you also take other liquid medicines or products, especially chlorpromazine or thioridazine liquids, do not take them at the same time you take Petol suspension. Ask your doctor how you should take them with Petol suspension.
• Eating grapefruit or drinking grapefruit juice may increase the risk of Petol suspension's side effects. Talk with your doctor before including grapefruit or grapefruit juice in your diet.
• Do not suddenly stop taking Petol suspension. You may have an increased risk of seizures. If you need to stop Petol suspension, your doctor will gradually lower your dose.
• Taking Petol suspension at the same time each day will help you remember to take it.
• Take Petol suspension on a regular schedule to get the most benefit from it.
• Continue to take Petol suspension even if you feel well. Do not miss any doses.
• If you miss a dose of Petol suspension, take it as soon as possible. If it is almost time for your next dose, skip the missed dose. Go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Petol suspension.

Petol is used to prevent and control seizures. This medication is known as an anticonvulsant or anti-epileptic drug. It is also used to relieve certain types of nerve pain (such as trigeminal neuralgia). This medication works by reducing the spread of seizure activity in the brain and restoring the normal balance of nerve activity.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to treat certain mental/mood conditions (such as bipolar disorder) and other types of nerve pain.

How to use Petol

Read the Medication Guide provided by your pharmacist before you start using Petol and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

If you are taking the extended-release tablets, take this medication by mouth with food as directed by your doctor, usually 2 times a day. Do not crush or chew extended-release tablets. Doing so can release all of the drug at once, increasing the risk of side effects. Also, do not split the tablets unless they have a score line and your doctor or pharmacist tells you to do so. Swallow the whole or split tablet without crushing or chewing. Inspect the tablets for chips and cracks. Do not take any damaged tablets.

If you are taking the extended-release capsules, take this medication by mouth with or without food as directed by your doctor, usually 2 times a day. Swallow the capsules whole. Do not crush or chew the capsules.

If you have trouble swallowing the capsules, you may open them and sprinkle the contents onto a teaspoonful of applesauce or other soft food. Swallow all of the drug/food mixture right away. Do not chew the mixture or prepare a supply in advance.

The dosage is based on your medical condition and response to treatment. To reduce your risk of side effects, your doctor may direct you to start this medication at a low dose and gradually increase your dose. Follow your doctor's instructions carefully.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor or pharmacist says you may do so safely. Grapefruit can increase the chance of side effects with this medicine. Ask your doctor or pharmacist for more details.

Take this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day. It is important to continue taking this medication even if you feel well.

Do not stop taking this medication without consulting your doctor. Some conditions (such as seizures) may become worse when this drug is suddenly stopped. Your dose may need to be gradually decreased.

Tell your doctor if your condition does not improve or if it worsens.

See also:
What other drugs will affect Petol?

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

Agents Highly Bound to Plasma Protein

Petol is not highly bound to plasma proteins; therefore, administration of Petol® (Petol extended-release) to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

Agents that Inhibits Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase

Petol is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active Petol 10,11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Therefore, the potential exists for interaction between Petol and any agent that inhibits CYP3A4 and/or epoxide hydrolase. Agents that are CYP3A4 inhibitors that have been found, or are expected, to increase plasma levels of Petol® (Petol extended-release) are the following:

Acetazolamide, azole antifungals, cimetidine, clarithromycin(1), dalfopristin, danazol, delavirdine, diltiazem, erythromycin(Phenytoin has also been reported to decrease in the presence of Petol. Careful monitoring of phenytoin plasma levels following co-medication with Petol is advised.

Thus, if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of the treatment with Petol® (Petol extended-release), it is reasonable to expect that a dose decrease for the concomitant agent may be necessary.

Pharmacological/Pharmacodynamic Interactions with Petol

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

Given the anticonvulsant properties of Petol, Petol® (Petol extended-release) may reduce the thyroid function as has been reported with other anticonvulsants. Additionally, anti-malarial drugs, such as chloroquine and mefloquine, may antagonize the activity of Petol.

Thus if a patient has been titrated to a stable dosage on one of the agents in this category, and then begins a course of treatment with Petol® (Petol extended-release), it is reasonable to expect that a dose adjustment may be necessary.

Because of its primary CNS effect, caution should be used when Petol (Petol extended-release) ® is taken with other centrally acting drugs and alcohol.

See also:
What are the possible side effects of Petol?

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

• Serious Dermatologic Reactions: Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome
• Aplastic anemia/agranulocytosis
• Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity
• Suicidal Behavior and Ideation
• Embryofetal Toxicity
• Abrupt Discontinuation and Seizure Risk
• Hyponatremia
• Cognitive and Motor Impairment
• Drug Interaction with Non-Nucleoside Reverse Transcriptase Inhibitors
• Liver Damage
• AV Heart Block
• Hepatic Porphyria
• Increased Intraocular Pressure

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most commonly reported adverse reactions (>5% in the Petol group and at least twice placebo) in the pooled 3-week placebo-controlled trials in patients with acute mania associated with Bipolar I Disorder (Studies 1 and 2) were dizziness, somnolence, nausea, vomiting, ataxia, constipation, pruritus, dry mouth, asthenia, blurred vision, and speech disorder. The Petol doses used were 400 to 1600 mg per day.

Table 2. Common Adverse Reactions Reported in Bipolar Disorder Studies 1 and 2 (Incidence > 2% and greater than placebo)

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Petol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System: confusion, diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, tinnitus.

Digestive System: gastric distress, abdominal pain, diarrhea, anorexia.

Laboratory Tests: thyroid function tests (T3, T4)- decreased values

Other: lupus erythematosus-like syndrome

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

Additional Adverse Reactions Associated With Petol

The following is a list of additional adverse reactions identified in clinical trials or postmarketing reports of other forms of Petol and not reported above for Petol. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Nervous System: Isolated cases of neuroleptic malignant syndrome have been reported in Petol use both with and without concomitant use of other psychotropic drugs.

Skin: onychomadesis, acute generalized exanthematous pustulosis (AGEP).

To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-8669VALIDUS(1-866-982-5438) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch