Cirulan

Each ampoule of injection contains anhydrous Cirulan (as Cirulan) 10 mg in 2 mL and sodium chloride in water for injections. When necessary, pH is adjusted with sodium hydroxide and/or hydrochloric acid.

Cirulan is 4-amino-5-chloro-N-(2-diethylaminoethyl)-2-methoxybenzamide HCl monohydrate. It has a molecular weight of 354.3 and its molecular formula is C₁₄H₂₂ClN₃O₂·HCl·H₂O.

Cirulan hydrochloride occurs as a white or almost white, crystalline powder or crystals, very soluble in water, freely soluble in alcohol, sparingly soluble in methylene chloride, practically insoluble in ether.

The use of Cirulan™ (Cirulan orally disintegrating tablets) is recommended for adults only. Therapy should not exceed 12 weeks in duration.

Symptomatic Gastroesophageal Reflux

Cirulan™ (Cirulan orally disintegrating tablets) is indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy.

The principal effect of Cirulan is on symptoms of postprandial and daytime heartburn with less observed effect on nocturnal symptoms. If symptoms are confined to particular situations, such as following the evening meal, use of Cirulan as single doses prior to the provocative situation should be considered, rather than using the drug throughout the day. Healing of esophageal ulcers and erosions has been endoscopically demonstrated at the end of a 12-week trial using doses of 15 mg four times daily. As there is no documented correlation between symptoms and healing of esophageal lesions, patients with documented lesions should be monitored endoscopically.

Diabetic Gastroparesis (Diabetic Gastric Stasis)

Cirulan™ (Cirulan orally disintegrating tablets) is indicated for the relief of symptoms associated with acute and recurrent diabetic gastric stasis. The usual manifestations of delayed gastric emptying (e.g., nausea, vomiting, heartburn, persistent fullness after meals, and anorexia) appear to respond to Cirulan within different time intervals.

Important Limitations

Cirulan™ (Cirulan orally disintegrating tablets) is indicated for adults only. Therapy should not exceed 12 weeks in duration. The safety and effectiveness in pediatric patients have not been established.

Cirulan is used to treat the symptoms of a certain type of stomach problem called gastroparesis in patients with diabetes. It works by increasing the movements or contractions of the stomach and intestines. It relieves symptoms such as nausea, vomiting, heartburn, a feeling of fullness after meals, and loss of appetite. Cirulan is also used to treat heartburn for patients with gastroesophageal reflux disease (GERD). GERD is esophageal irritation from the backward flow of gastric acid into the esophagus.

Cirulan 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, Cirulan is used in certain patients with the following medical conditions:

• Failure of the stomach to empty its contents.
• Nausea and vomiting caused by other medicines.
• Persistent hiccups.
• Prevention of aspirating fluid into the lungs during surgery.
• Vascular headaches.

Therapy with Cirulan™ (Cirulan orally disintegrating tablets) should not exceed 12 weeks in duration.

Instructions for Use/Handling Cirulan™ (Cirulan orally disintegrating tablets)

Just prior to administration, remove the Cirulan™ (Cirulan orally disintegrating tablets) orally disintegrating tablet from the packaging with dry hands. The tablet should be removed from the package and immediately placed on the tongue, to disintegrate and be swallowed with the saliva. The tablet typically disintegrates in about one and one-half minutes. Administration with liquid is not necessary.

Symptomatic Gastroesophageal Reflux Disease

For the relief of symptomatic, documented gastroesophageal reflux disease (GERD), therapy should not exceed 12 weeks.

Administer from 10 mg to 15 mg of Cirulan™ (Cirulan orally disintegrating tablets) orally up to four times daily, 30 minutes before each meal and at bedtime, depending upon symptoms being treated and clinical response. If symptoms occur only intermittently or at specific times of the day, use of Cirulan in single doses up to 20 mg prior to the provoking situation may be preferred rather than continuous treatment. Occasionally, patients (such as elderly patients) who are more sensitive to the therapeutic or adverse effects of Cirulan will require only 5 mg per dose.

Experience with esophageal erosions and ulcerations is limited, but healing has thus far been documented in one controlled trial using four times daily therapy at 15 mg/dose, and this regimen should be used when lesions are present, so long as it is tolerated. Because of the poor correlation between symptoms and endoscopic appearance of the esophagus, therapy directed at esophageal lesions is best guided by endoscopic evaluation.

Prolonged treatment ( > 12 weeks) with Cirulan should be avoided in all but rare cases where therapeutic benefit is thought to counterbalance the risks to the patient of developing tardive dyskinesia..

Diabetic Gastroparesis (Diabetic Gastric Stasis)

For the relief of symptoms associated with diabetic gastroparesis (diabetic gastric stasis), therapy of two to eight weeks is recommended. Therapy should not exceed 12 weeks in duration.

Administer 10 mg of Cirulan™ (Cirulan orally disintegrating tablets) 30 minutes before each meal and at bedtime for two to eight weeks, depending upon response and the likelihood of continued well-being upon drug discontinuation.

The initial route of administration should be determined by the severity of the presenting symptoms. If only the earliest manifestations of diabetic gastric stasis are present, oral administration of Cirulan™ (Cirulan orally disintegrating tablets) may be initiated. However, if severe symptoms are present, therapy should begin with Cirulan injection (consult labeling of the injection prior to initiating parenteral administration).

Administration of Cirulan injection up to 10 days may be required before symptoms subside, at which time oral administration may be instituted. Since diabetic gastric stasis is frequently recurrent, Cirulan™ (Cirulan orally disintegrating tablets) therapy should be reinstituted at the earliest manifestation.

Patients with Renal Impairment

Since Cirulan is excreted principally through the kidneys, in those patients whose creatinine clearance is below 40 mL/min, therapy should be initiated at approximately one-half the recommended dosage. Depending upon clinical efficacy and safety considerations, the dosage may be increased or decreased as appropriate.

How supplied

Dosage Forms And Strengths

Cirulan™ (Cirulan) orally disintegrating tablets contains either 5 mg or 10 mg of Cirulan base (as monohydrochloride monohydrate). The tablets are white, round, flat-faced, and orange flavored.

Cirulan™ (Cirulan) orally disintegrating tablets 5 mg base (as the monohydrochloride monohydrate) are white, round, flat-faced, orange-flavored and engraved "AP" on one side and "152" on the other side. They are supplied as follows:

Bottles of 100..................NDC 68220-152-10

Cirulan™ (Cirulan) orally disintegrating tablets 10 mg base (as the monohydrochloride monohydrate) are white, round, flat-faced, orange-flavored and engraved "AP"on one side and "153" on the other side. They are supplied as follows:

Bottles of 100..................NDC 68220-153-10

Storage and Handling

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

Dispense in a tight, light-resistant container as defined in the USP/NF.

Manufactured for: Alaven Pharmaceuticals LLC., Marietta, GA 30062. www.alavenpharm.com. For Medical Inquiries, call toll-free 1-888-317-0001. Manufactured by: CIMA® LABS INC.

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

NEVER TAKE Cirulan IN LARGER AMOUNTS THAN RECOMMENDED, OR FOR LONGER THAN 12 WEEKS. High doses or long-term use of Cirulan can cause a serious movement disorder that may not be reversible. Symptoms of this disorder include uncontrollable muscle movements of your lips, tongue, eyes, face, arms, or legs. The longer you take Cirulan, the more likely you are to develop a serious movement disorder. The risk of this side effect is higher in women, diabetics, and older adults.

You should not take this medication if you are allergic to Cirulan, or if you have bleeding or blockage in your stomach or intestines, epilepsy or other seizure disorder, or an adrenal gland tumor (pheochromocytoma).

Before you take Cirulan, tell your doctor if you have kidney or liver disease, congestive heart failure, high blood pressure, diabetes, Parkinson's disease, or a history of depression.

Do not drink alcohol. It can increase some of the side effects of Cirulan.

There are many other medicines that can interact with Cirulan. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Stop using Cirulan and call your doctor at once if you have tremors or uncontrolled muscle movements, fever, stiff muscles, confusion, sweating, fast or uneven heartbeats, rapid breathing, depressed mood, thoughts of suicide or hurting yourself, hallucinations, anxiety, agitation, seizure, or jaundice (yellowing of your skin or eyes).

Use Cirulan orally disintegrating tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Cirulan orally disintegrating tablets comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Cirulan orally disintegrating tablets refilled.
• Take Cirulan orally disintegrating tablets by mouth 30 minutes before meals and at bedtime without food or water unless directed otherwise by your doctor.
• Do not remove the tablet from the blister pack until you are ready to take Cirulan orally disintegrating tablets. Make sure that your hands are dry when you open the blister pack. If the tablet breaks or crumbles while handling, discard and remove a new tablet. Place the tablet on your tongue. The tablet dissolves quickly and can be swallowed with saliva. Take the tablet immediately after opening the blister pack. Do not store the removed tablet for future use.
• It may take several days to weeks for Cirulan orally disintegrating tablets to work. Do not stop taking Cirulan orally disintegrating tablets without checking with your doctor.
• If you miss a dose of Cirulan orally disintegrating tablets, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and 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 Cirulan orally disintegrating tablets.

This medication is used to treat certain conditions of the stomach and intestines. Cirulan is used as a short-term treatment (4 to 12 weeks) for persistent heartburn when the usual medicines do not work well enough. It is used mostly for heartburn that occurs after a meal or during the daytime. Treating persistent heartburn can decrease the damage done by stomach acid to the swallowing tube (esophagus) and help healing.

Cirulan is also used in diabetic patients who have poor emptying of their stomachs (gastroparesis). Treating gastroparesis can decrease symptoms of nausea, vomiting, and stomach/abdominal fullness. Cirulan works by blocking a natural substance (dopamine). It speeds up stomach emptying and movement of the upper intestines.

This drug is not recommended for use in children younger than 1 year due to an increased risk of serious side effects (such as muscle spasms/uncontrolled muscle movements). Ask the doctor or pharmacist for details.

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 prevent nausea/vomiting from chemotherapy or radiation treatments for cancer.

How to use Cirulan

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

Take this medication by mouth 30 minutes before meals and at bedtime, usually 4 times daily or exactly as directed by your doctor. If you are using the liquid form of this medication, carefully measure the dose using a special measuring device/spoon. Do not use a household spoon because you may not get the correct dose.

If you are using the disintegrating tablet, do not remove the tablet from the blister pack until right before your dose. Dry your hands before using this medication. Do not use the tablet if it is broken or crumbled. Immediately after removing the tablet, place it on the tongue. Allow it to dissolve completely, then swallow it with saliva. You do not need to take this product with water.

Dosage is based on your weight, medical condition, and response to treatment. If heartburn only occurs at certain times (such as after the evening meal), your doctor may direct you to take a single dose before those times instead of taking it throughout the day. This will reduce your risk of side effects.

Because of the risk of tardive dyskinesia, do not take this more often, in larger doses, or for longer than directed by your doctor. According to the manufacturer, treatment should not exceed 12 weeks.

To treat diabetic gastroparesis, this medication is usually taken for 2 to 8 weeks until your gut is working well. This condition may recur from time to time. Your doctor may direct you to start taking this medication as soon as your symptoms reappear and stop when you feel better. Ask your doctor for directions for starting and stopping this medication.

Take this medication regularly as directed to get the most benefit from it. To help you remember, take it at the same times before a meal each day.

If this medication has been used regularly for a long time or in high doses, withdrawal symptoms (such as dizziness, nervousness, headaches) may occur if you suddenly stop using this medication. To prevent withdrawal reactions, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for more details, and report any withdrawal reactions right away.

Tell your doctor if your condition persists or worsens.

See also:
What other drugs will affect Cirulan?

Anticholinergic Agents: May diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Cirulan may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Monitor therapy

Antipsychotic Agents: Cirulan may enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

Atovaquone: Cirulan may decrease the serum concentration of Atovaquone. Management: Consider alternatives to Cirulan when possible; atovaquone should only be used with Cirulan if no other antiemetics are available. Consider therapy modification

CycloSPORINE (Systemic): Cirulan may increase the absorption of CycloSPORINE (Systemic). Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Cirulan. Management: Reduce Cirulan dose to 5 mg 4 times daily (30 minutes before each meal and at bedtime) and limit the maximum daily dose to 20 mg if combined with strong CYP2D6 inhibitors. Consider therapy modification

Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

Deutetrabenazine: May enhance the adverse/toxic effect of Cirulan. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Monitor therapy

Droperidol: May enhance the adverse/toxic effect of Cirulan. Avoid combination

Fosfomycin: Gastrointestinal Agents (Prokinetic) may decrease the serum concentration of Fosfomycin. Monitor therapy

Levosulpiride: Benzamide Derivatives may enhance the adverse/toxic effect of Levosulpiride. Monitor therapy

Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Cirulan. Management: Seek alternatives to this combination when possible. Monitor patients receiving Cirulan with metyrosine for development of extrapyramidal symptoms. Consider therapy modification

Monoamine Oxidase Inhibitors: Cirulan may enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Avoid combination

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Opioid Agonists: May diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy

Posaconazole: Cirulan may decrease the serum concentration of Posaconazole. Monitor therapy

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

Promethazine: Cirulan may enhance the adverse/toxic effect of Promethazine. Avoid combination

Quinagolide: Cirulan may diminish the therapeutic effect of Quinagolide. Monitor therapy

Rivastigmine: May enhance the adverse/toxic effect of Cirulan. Specifically, the risk of extrapyramidal adverse reactions may be increased with this combination. Avoid combination

Selective Serotonin Reuptake Inhibitors: Cirulan may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving Cirulan with selective serotonin reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: Cirulan may enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving Cirulan with serotonin/norepinephrine reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

Tacrolimus (Systemic): Cirulan may increase the serum concentration of Tacrolimus (Systemic). Specifically, treatment of gastroparesis may increase tacrolimus concentrations. Monitor therapy

Tetrabenazine: Cirulan may enhance the adverse/toxic effect of Tetrabenazine. Avoid combination

Thiopental: Cirulan may enhance the therapeutic effect of Thiopental. Management: Consider thiopental dose reduction when used concomitantly with Cirulan. Monitor patient response to treatment closely if using this combination. Consider therapy modification

Tricyclic Antidepressants: Cirulan may enhance the adverse/toxic effect of Tricyclic Antidepressants. Management: Seek alternatives to this combination when possible. Monitor patients receiving Cirulan with tricyclic antidepressants for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

Trimetazidine: Cirulan may enhance the adverse/toxic effect of Trimetazidine. Specifically, the risk of extrapyramidal symptoms may be enhanced. Avoid combination

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

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 studies of another drug and may not reflect the rates observed in clinical practice.

A total of 86 subjects entered three studies with Cirulan; 12 subjects entered a pilot bioavailability study (BA); 44 subjects entered a bioequivalence (BE) study, and 30 subjects entered a food-effect study. The adverse reactions from the BE and food-effect study are summarized in Table 1. The pilot BA study data are not included because it was performed with a formulation different from the Cirulan formulation.

The adverse experience profile seen with Cirulan was similar to Cirulan tablets. Thirty-three (33) adverse reactions were reported after receiving Cirulan and 30 adverse reactions were reported after receiving Cirulan tablets.

Table 1: Adverse Reactions in BE and Food-Effect Study in ≥ 2% of Subjects

The most frequently reported adverse reactions (greater than 2%) associated with Cirulan were: nausea, vomiting, fatigue, somnolence and headache. The most frequently reported adverse reactions (greater than 2%) associated with Cirulan tablets were: nausea, headache, fatigue, somnolence, and dizziness. The combined data from the fasted BE study and the food-effect study did not demonstrate any significant differences in the adverse event profile for Cirulan compared to Cirulan tablets.

Post-Marketing Experience

The following adverse reactions are from the cumulative post-marketing experience with Cirulan tablets. Since the 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.

CNS Effects: Restlessness, drowsiness, fatigue, and lassitude occur in approximately 10% of patients receiving the most commonly prescribed dosage of 10 mg four times a day. Insomnia, headache, confusion, dizziness, or depression with suicidal ideation occurs less frequently. The incidence of drowsiness is greater at higher doses. There are isolated reports of seizures without clear-cut relationship to Cirulan. Rarely, hallucinations have been reported.

Extrapyramidal Syndromes (EPS): Acute dystonic reactions, the most common type of EPS associated with Cirulan, occur in approximately 0.2% of patients (1 in 500) treated with 30 to 40 mg of Cirulan per day. Symptoms include involuntary movements of limbs, facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of tongue, bulbar type of speech, trismus, opisthotonus (tetanus-like reactions), and rarely, stridor and dyspnea possibly due to laryngospasm; ordinarily these symptoms are readily reversed by diphenhydramine.

Drug-induced Parkinsonian-like symptoms may include bradykinesia, tremor, cogwheel rigidity, mask-like facies.

Tardive dyskinesia is most frequently characterized by involuntary movements of the tongue, face, mouth, or jaw, and sometimes by involuntary movements of the trunk and/or extremities; movements may be choreoathetotic in appearance. Motor restlessness (akathisia) may include inability to sit still, pacing, and foot tapping. These symptoms may disappear spontaneously or respond to a reduction in dosage.

Neuroleptic Malignant Syndrome: Rare occurrences of Neuroleptic Malignant Syndrome (NMS) have been reported.

Endocrine Disturbances: Galactorrhea, amenorrhea, gynecomastia, and impotence secondary to hyperprolactinemia. Fluid retention secondary to transient elevation of aldosterone.

Cardiovascular: Hypotension, hypertension, supraventricular tachycardia, bradycardia, fluid retention, acute congestive heart failure, possible AV block.

Gastrointestinal: Nausea, bowel disturbances, primarily diarrhea.

Hepatic: Rarely, cases of hepatotoxicity characterized by such findings as jaundice and altered liver function tests, when Cirulan was administered with other drugs with known hepatotoxic potential.

Renal: Urinary frequency and incontinence.

Hematologic: A few cases of neutropenia, leukopenia, or agranulocytosis, generally without clear-cut relationship to Cirulan. Methemoglobinemia in adults and especially with overdosage in neonates. Sulfhemoglobinemia in adults.

Allergic Reactions: A few cases of rash, urticaria, or bronchospasm, especially in patients with a history of asthma. Rarely, angioneurotic edema, including glossal or laryngeal edema.

Miscellaneous: Visual disturbances. Porphyria.