Cyclobenzaprine

Dosage Form: tablet
Cyclobenzaprine HYDROCHLORIDE TABLETS, USP Rx only

Cyclobenzaprine Description

Cyclobenzaprine hydrochloride, USP is a white to off-white, odorless crystalline powder with the molecular formula C20H21N•HCl and a molecular weight of 311.9. It has a melting point of 217° C, and a pKa of 8.47 at 25° C. It is freely soluble in water, in alcohol and in methanol, sparingly soluble in isopropanol, slightly soluble in chloroform and in methylene chloride and insoluble in hydrocarbon solvents. If aqueous solutions are made alkaline, the free base separates. Cyclobenzaprine HCl is designated chemically as 3-(5H-dibenzo[a,d ] cyclohepten-5-ylidene)-N, N-dimethyl-1-propanamine hydrochloride, and has the following structural formula:

Cyclobenzaprine hydrochloride tablets, USP are supplied as a 7.5 mg tablets for oral administration. Cyclobenzaprine hydrochloride 7.5 mg tablets contain the following inactive ingredients: corn starch, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, pregelatinised starch, talc and titanium dioxide.

Cyclobenzaprine - Clinical Pharmacology

Cyclobenzaprine HCl relieves skeletal muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm due to central nervous system disease.

Cyclobenzaprine reduced or abolished skeletal muscle hyperactivity in several animal models. Animal studies indicate that Cyclobenzaprine does not act at the neuromuscular junction or directly on skeletal muscle. Such studies show that Cyclobenzaprine acts primarily within the central nervous system at brain stem as opposed to spinal cord levels, although its action on the latter may contribute to its overall skeletal muscle relaxant activity. Evidence suggests that the net effect of Cyclobenzaprine is a reduction of tonic somatic motor activity, influencing both gamma (g) and alpha (μ) motor systems.

Pharmacological studies in animals showed a similarity between the effects of Cyclobenzaprine and the structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Cyclobenzaprine caused slight to moderate increase in heart rate in animals.

Pharmacokinetics

Estimates of mean oral bioavailability of Cyclobenzaprine range from 33% to 55%. Cyclobenzaprine exhibits linear pharmacokinetics over the dose range 2.5 mg to 10 mg, and is subject to enterohepatic circulation. It is highly bound to plasma proteins. Drug accumulates when dosed three times a day, reaching steady-state within 3 to 4 days at plasma concentrations about four-fold higher than after a single dose. At steady state in healthy subjects receiving 10 mg t.i.d. (n = 18), peak plasma concentration was 25.9 ng/mL (range, 12.8 to 46.1 ng/mL), and area under the concentration-time (AUC) curve over an 8-hour dosing interval was 177 ng.hr/mL (range, 80 to 319 ng.hr/mL).

Cyclobenzaprine is extensively metabolized, and is excreted primarily as glucuronides via the kidney.

Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for Cyclobenzaprine. Cyclobenzaprine is eliminated quite slowly, with an effective half-life of 18 hours (range 8 to 37 hours; n = 18); plasma clearance is 0.7 L/min.

The plasma concentration of Cyclobenzaprine is generally higher in the elderly and in patients with hepatic impairment. (See PRECAUTIONS, Use in the Elderly and PRECAUTIONS, Impaired Hepatic Function.)

Elderly

In a pharmacokinetic study in elderly individuals (≥ 65yrs old), mean (n = 10) steady-state Cyclobenzaprine AUC values were approximately 1.7 fold (171 ng.hr/mL, range 96.1 to 255.3) higher than those seen in a group of eighteen younger adults (101.4 ng.hr/mL, range 36.1 to 182.9) from another study. Elderly male subjects had the highest observed mean increase, approximately 2.4 fold (198.3 ng.hr/mL, range 155.6 to 255.3 versus 83.2 ng.hr/mL, range 41.1 to 142.5 for younger males) while levels in elderly females were increased to a much lesser extent, approximately 1.2 fold (143.8 ng.hr/mL, range 96.1 to 196.3 versus 115.9 ng.hr/mL, range 36.1 to 182.9 for younger females).

In light of these findings, therapy with Cyclobenzaprine hydrochloride in the elderly should be initiated with a 5 mg dose and titrated slowly upward.

Hepatic Impairment

In a pharmacokinetic study of sixteen subjects with hepatic impairment (15 mild, 1 moderate per Child- Pugh score), both AUC and Cmax were approximately double the values seen in the healthy control group. Based on the findings, Cyclobenzaprine should be used with caution in subjects with mild hepatic impairment starting with the 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of Cyclobenzaprine in subjects with moderate to severe impairment is not recommended.

No significant effect on plasma levels or bioavailability of Cyclobenzaprine or aspirin was noted when single or multiple doses of the two drugs were administered concomitantly. Concomitant administration of Cyclobenzaprine hydrochloride and naproxen or diflunisal was well tolerated with no reported unexpected adverse effects. However combination therapy of Cyclobenzaprine hydrochloride with naproxen was associated with more side effects than therapy with naproxen alone, primarily in the form of drowsiness. No well-controlled studies have been performed to indicate that Cyclobenzaprine hydrochloride enhances the clinical effect of aspirin or other analgesics, or whether analgesics enhance the clinical effect of Cyclobenzaprine hydrochloride in acute musculoskeletal conditions.

Clinical Studies

Eight double-blind controlled clinical studies were performed in 642 patients comparing Cyclobenzaprine hydrochloride 10 mg, diazepam**, and placebo. Muscle spasm, local pain and tenderness, limitation of motion, and restriction in activities of daily living were evaluated. In three of these studies there was a significantly greater improvement with Cyclobenzaprine hydrochloride than with diazepam, while in the other studies the improvement following both treatments was comparable.

Although the frequency and severity of adverse reactions observed in patients treated with Cyclobenzaprine hydrochloride were comparable to those observed in patients treated with diazepam, dry mouth was observed more frequently in patients treated with Cyclobenzaprine hydrochloride and dizziness more frequently in those treated with diazepam. The incidence of drowsiness, the most frequent adverse reaction, was similar with both drugs.

The efficacy of Cyclobenzaprine hydrochloride 5 mg was demonstrated in two seven-day, double-blind, controlled clinical trials enrolling 1405 patients. One study compared Cyclobenzaprine hydrochloride 5 mg and 10 mg t.i.d. to placebo; and a second study compared Cyclobenzaprine hydrochloride 5 mg and 2.5 mg t.i.d. to placebo. Primary endpoints for both trials were determined by patient-generated data and included global impression of change, medication helpfulness, and relief from starting backache. Each endpoint consisted of a score on a 5-point rating scale (from 0 or worst outcome to 4 or best outcome). Secondary endpoints included a physician’s evaluation of the presence and extent of palpable muscle spasm.

Comparisons of Cyclobenzaprine hydrochloride 5 mg and placebo groups in both trials established the statistically significant superiority of the 5 mg dose for all three primary endpoints at day 8 and, in the study comparing 5 and 10 mg, at day 3 or 4 as well. A similar effect was observed with Cyclobenzaprine hydrochloride 10 mg (all endpoints). Physician-assessed secondary endpoints also showed that Cyclobenzaprine hydrochloride 5 mg was associated with a greater reduction in palpable muscle spasm than placebo.

Analysis of the data from controlled studies shows that Cyclobenzaprine hydrochloride produces clinical improvement whether or not sedation occurs.

Surveillance Program

A postmarketing surveillance program was carried out in 7607 patients with acute musculoskeletal disorders, and included 297 patients treated with Cyclobenzaprine hydrochloride 10 mg for 30 days or longer. The overall effectiveness of Cyclobenzaprine hydrochloride was similar to that observed in the double-blind controlled studies; the overall incidence of adverse effects was less (see ADVERSE REACTIONS).

Indications and Usage for Cyclobenzaprine

Cyclobenzaprine hydrochloride tablets, USP are indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, limitation of motion, and restriction in activities of daily living.

Cyclobenzaprine hydrochloride tablets, USP are should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted.

Cyclobenzaprine hydrochloride tablets, USP have not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease, or in children with cerebral palsy.

Contraindications

Hypersensitivity to any component of this product.

Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation.

Hyperpyretic crisis seizures, and deaths have occurred in patients receiving Cyclobenzaprine (or structurally similar tricyclic antidepressants) concomitantly with MAO inhibitor drugs.

Acute recovery phase of myocardial infarction, and patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure.

Hyperthyroidism.

Warnings

Cyclobenzaprine is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred (see WARNINGS, below, and ADVERSE REACTIONS).

Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke.

Cyclobenzaprine hydrochloride may enhance the effects of alcohol, barbiturates, and other CNS depressants.

Precautions

General

Because of its atropine-like action, Cyclobenzaprine hydrochloride should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication.

Impaired Hepatic Function

The plasma concentration of Cyclobenzaprine is increased in patients with hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Hepatic Impairment). These patients are generally more susceptible to drugs with potentially sedating effects, including Cyclobenzaprine.

Cyclobenzaprine hydrochloride should be used with caution in subjects with mild hepatic impairment starting with a 5 mg dose and titrating slowly upward. Due to the lack of data in subjects with more severe hepatic insufficiency, the use of Cyclobenzaprine hydrochloride in subjects with moderate to severe impairment is not recommended.

Information for Patients

Cyclobenzaprine hydrochloride, especially when used with alcohol or other CNS depressants, may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. In the elderly, the frequency and severity of adverse events associated with the use of Cyclobenzaprine, with or without concomitant medications, is increased. In elderly patients, Cyclobenzaprine hydrochloride should be initiated with a 5 mg dose and titrated slowly upward.

Drug Interactions

Cyclobenzaprine hydrochloride may have life-threatening interactions with MAO inhibitors. (See CONTRAINDICATIONS.)

Cyclobenzaprine hydrochloride may enhance the effects of alcohol, barbiturates, and other CNS depressants.

Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds.

Tricyclic antidepressants may enhance the seizure risk in patients taking tramadol.†

Carcinogenesis, Mutagenesis, Impairment of Fertility

In rats treated with Cyclobenzaprine hydrochloride for up to 67 weeks at doses of approximately 5 to 40 times the maximum recommended human dose, pale, sometimes enlarged, livers were noted and there was a dose-related hepatocyte vacuolation with lipidosis. In the higher dose groups this microscopic change was seen after 26 weeks and even earlier in rats which died prior to 26 weeks; at lower doses, the change was not seen until after 26 weeks.

Cyclobenzaprine did not affect the onset, incidence or distribution of neoplasia in an 81-week study in the mouse or in a 105-week study in the rat.

At oral doses of up to 10 times the human dose, Cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. Cyclobenzaprine did not demonstrate mutagenic activity in the male mouse at dose levels of up to 20 times the human dose.

Pregnancy

Pregnancy Category B: Reproduction studies have been performed in rats, mice and rabbits at doses up to 20 times the human dose, and have revealed no evidence of impaired fertility or harm to the fetus due to Cyclobenzaprine hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because Cyclobenzaprine is closely related to the tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when Cyclobenzaprine hydrochloride is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Cyclobenzaprine hydrochloride in pediatric patients below 15 years of age have not been established.

Use in the Elderly

The plasma concentration of Cyclobenzaprine is increased in the elderly (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Elderly). The elderly may also be more at risk for CNS adverse events such as hallucinations and confusion, cardiac events resulting in falls or other sequelae, drug-drug and drug-disease interactions. For these reasons, in the elderly, Cyclobenzaprine should be used only if clearly needed. In such patients Cyclobenzaprine hydrochloride should be initiated with a 5 mg dose and titrated slowly upward.

Adverse Reactions

Incidence of most common adverse reactions in the 2 double-blind‡, placebo-controlled 5 mg studies (incidence of > 3% on Cyclobenzaprine hydrochloride 5 mg):

	Cyclobenzaprine Hydrochloride 5 mg N=464	Cyclobenzaprine Hydrochloride 10 mg N=249	Placebo N=469
Drowsiness	29%	38%	10%
Dry Mouth	21%	32%	7%
Fatigue	6%	6%	3%
Headache	5%	5%	8%

Adverse reactions which were reported in 1% to 3% of the patients were: abdominal pain, acid regurgitation, constipation, diarrhea, dizziness, nausea, irritability, mental acuity decreased, nervousness, upper respiratory infection, and pharyngitis.


The following list of adverse reactions is based on the experience in 473 patients treated with Cyclobenzaprine hydrochloride 10 mg in additional controlled clinical studies, 7607 patients in the postmarketing surveillance program, and reports received since the drug was marketed. The overall incidence of adverse reactions among patients in the surveillance program was less than the incidence in the controlled clinical studies.


The adverse reactions reported most frequently with Cyclobenzaprine hydrochloride were drowsiness, dry mouth and dizziness. The incidence of these common adverse reactions was lower in the surveillance program than in the controlled clinical studies:


‡ Note: Cyclobenzaprine hydrochloride 10 mg data are from one clinical trial. Cyclobenzaprine hydrochloride 5 mg and placebo data are from two studies.

	Clinical Studies With Cyclobenzaprine Hydrochloride 10 mg	Surveillance Program With Cyclobenzaprine Hydrochloride 10 mg
Drowsiness	39%	16%
Dry Mouth	27%	7%
Dizziness	11%	3%

Among the less frequent adverse reactions, there was no appreciable difference in incidence in controlled clinical studies or in the surveillance program. Adverse reactions which were reported in 1% to 3% of the patients were: fatigue/tiredness, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion.


The following adverse reactions have been reported in postmarketing experience or with an incidence of less than 1% of patients in clinical trials with the 10 mg tablet:


Body as a Whole: Syncope; malaise.


Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension.


Digestive: Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function and rare reports of hepatitis, jaundice and cholestasis.


Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash.


Musculoskeletal: Local weakness.


Nervous System and Psychiatric: Seizures, ataxia; vertigo; dysarthria; tremors; hypertonia; convulsions; muscle twitching; disorientation; insomnia; depressed mood; abnormal sensations; anxiety; agitation; psychosis, abnormal thinking and dreaming; hallucinations; excitement; paresthesia; diplopia.


Skin: Sweating.


Special Senses: Ageusia; tinnitus.


Urogenital: Urinary frequency and/or retention.


Causal Relationship Unknown

Other reactions, reported rarely for Cyclobenzaprine hydrochloride under circumstances where a causal relationship could not be established or reported for other tricyclic drugs, are listed to serve as alerting information to physicians:


Body as a whole: Chest pain; edema.


Cardiovascular: Hypertension; myocardial infarction; heart block; stroke.


Digestive: Paralytic ileus, tongue discoloration; stomatitis; parotid swelling.


Endocrine: Inappropriate ADH syndrome.


Hematic and Lymphatic: Purpura; bone marrow depression; leukopenia; eosinophilia; thrombocytopenia.


Metabolic, Nutritional and Immune: Elevation and lowering of blood sugar levels; weight gain or loss.


Musculoskeletal: Myalgia.


Nervous System and Psychiatric: Decreased or increased libido; abnormal gait; delusions; aggressive behavior; paranoia; peripheral neuropathy; Bell’s palsy; alteration in EEG patterns; extrapyramidal symptoms.


Respiratory: Dyspnea.


Skin: Photosensitization; alopecia.


Urogenital: Impaired urination; dilatation of urinary tract; impotence; testicular swelling; gynecomastia; breast enlargement; galactorrhea.

Drug Abuse and Dependence

Pharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when Cyclobenzaprine hydrochloride is administered, even though they have not been reported to occur with this drug. Abrupt cessation of treatment after prolonged administration rarely may produce nausea, headache, and malaise. These are not indicative of addiction.

Overdosage

Although rare, deaths may occur from overdosage with Cyclobenzaprine hydrochloride. Multiple drug ingestion (including alcohol) is common in deliberate Cyclobenzaprine overdose. As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity may develop rapidly after Cyclobenzaprine overdose; therefore, hospital monitoring is required as soon as possible. The acute oral LD50 of Cyclobenzaprine hydrochloride is approximately 338 and 425 mg/kg in mice and rats, respectively.

MANIFESTATIONS

The most common effects associated with Cyclobenzaprine overdose are drowsiness and tachycardia. Less frequent manifestations include tremor, agitation, coma, ataxia, hypertension, slurred speech, confusion, dizziness, nausea, vomiting, and hallucinations. Rare but potentially critical manifestations of overdose are cardiac arrest, chest pain, cardiac dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome.

Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of Cyclobenzaprine toxicity.

Other potential effects of overdosage include any of the symptoms listed under ADVERSE REACTIONS.

MANAGEMENT


General

As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment.


In order to protect against the rare but potentially critical manifestations described above, obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an intravenous line and initiate gastric decontamination. Observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. Monitoring of plasma drug levels should not guide management of the patient. Dialysis is probably of no value because of low plasma concentrations of the drug.

Gastrointestinal Decontamination

All patients suspected of an overdose with Cyclobenzaprine hydrochloride should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage and emesis is contraindicated.

Cardiovascular

A maximal limb-lead QRS duration of greater/equal than 0.10 seconds may be the best indication of the severity of the overdose. Serum alkalinization, to a pH of 7.45 to 7.55, using intravenous sodium bicarbonate and hyperventilation (as needed), should be instituted for patients with dysrhythmias and/or QRS widening.  A pH greater than 7.60 or a pCO2 less than 20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

CNS

In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines or, if these are ineffective, other anticonvulsants (e.g. phenobarbital, phenytoin). Physostigmine is not recommended except to treat lifethreatening symptoms that have been unresponsive to other therapies, and then only in close consultation with a poison control center.

PSYCHIATRIC FOLLOW-UP

Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

PEDIATRIC MANAGEMENT

The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

Cyclobenzaprine Dosage and Administration

For most patients, the recommended dose of Cyclobenzaprine hydrochloride tablets is 5 mg three times a day. Based on individual patient response, the dose may be increased to either 7.5 or 10 mg three times a day. Use of Cyclobenzaprine hydrochloride tablets for periods longer than two or three weeks is not recommended. (see INDICATIONS AND USAGE).

Less frequent dosing should be considered for hepatically impaired or elderly patients (see PRECAUTIONS, Impaired Hepatic Function, and Use in the Elderly).

How is Cyclobenzaprine Supplied

Cyclobenzaprine hydrochloride tablets, USP are available in 7.5 mg strength. The dosage strength is supplied as follows:

The 7.5 mg tablets are white, round shaped, biconvex, film coated tablets debossed with ‘RE’ on one side and ‘33’ on the other side.

NDC 76218-1219-1 Bottles of 1000

Store between 20° - 25° C (68° - 77° F) [See USP controlled room temperature]

You may report side effects to FDA at 1-800-FDA-1088.

Distributed by:

KLE 2 Inc

3731 S. Robertson Blvd

Culver City, CA 90232

August 2011

Label For Cyclobenzaprine HYDROCHLORIDE TABLETS, USP

Cyclobenzaprine HYROCHLORIDE  Cyclobenzaprine hydrochloride  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 76218-1219 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Cyclobenzaprine HYDROCHLORIDE (Cyclobenzaprine) Cyclobenzaprine HYDROCHLORIDE 7.5 mg

Inactive Ingredients Ingredient Name Strength STARCH, CORN   HYDROXYPROPYL CELLULOSE   HYPROMELLOSES   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE   POLYETHYLENE GLYCOLS   TALC   TITANIUM DIOXIDE

Product Characteristics Color white (WHITE) Score no score Shape ROUND (Biconvex) Size 7mm Flavor Imprint Code RE;33 Contains

Packaging # NDC Package Description Multilevel Packaging 1 76218-1219-1 1000 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA078722	08/29/2011

Labeler - KLE 2, Inc. (017646153)

Revised: 08/2011KLE 2, Inc.

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Cycloset

bromocriptine mesylate

Dosage Form: tablet
FULL PRESCRIBING INFORMATION

Indications and Usage for Cycloset

Type 2 diabetes mellitus

Cycloset is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use

• Cycloset should not be used to treat type 1 diabetes or diabetic ketoacidosis.


• Limited efficacy data in combination with thiazolidinediones


• Efficacy has not been confirmed in combination with insulin.

Cycloset Dosage and Administration

Recommended Dosing

The recommended dose of Cycloset is 1.6 mg to 4.8 mg administered once daily within two hours after waking in the morning. Cycloset should be taken with food to potentially reduce gastrointestinal side effects such as nausea.

Titration

Cycloset should be initiated at one tablet (0.8 mg) and increased by one tablet per week until a maximum daily dose of 6 tablets (4.8 mg) or until the maximal tolerated number of tablets between 2 and 6 per day is reached.

Dosage Forms and Strengths

0.8 mg tablets are white and round, imprinted with "C" on one side and "9" on the other.

Contraindications

Cycloset is contraindicated in

• Patients with known hypersensitivity to bromocriptine, ergot-related drugs, or any of the excipients in Cycloset.


• Patients with syncopal migraine. Bromocriptine increases the likelihood of a hypotensive episode among patients with syncopal migraine. Loss of consciousness during a migraine may reflect dopamine receptor hypersensitivity. Cycloset is a dopamine receptor agonist, and may, therefore, potentiate the risk for syncope in these patients.


• Women who are nursing their children. Cycloset may inhibit lactation. There are postmarketing reports of stroke in this patient population although causality has not been proven [See Nursing Mothers (8.3)].

Warnings and Precautions

Hypotension

Hypotension, including orthostatic hypotension, can occur, particularly upon initiation of Cycloset therapy and with dose escalation. In a 52-week, randomized clinical trial of 3070 patients, hypotension was reported in 2.2% of patients randomized to Cycloset compared to 0.8% of patients randomized to placebo. Among Cycloset-treated patients reporting symptomatic hypotension, 98% were on at least one blood pressure medication compared to 73% on such medication in the total study population. In this trial, six Cycloset-treated patients (0.3%) reported an adverse event of orthostatic hypotension compared to 2 (0.2%) placebo-treated patients. All six patients were taking anti-hypertensive medications. Hypotension can result in syncope. In this trial, syncope due to any cause was reported in 1.6% of Cycloset-treated patients and 0.7% of placebo-treated patients [See Adverse Reactions (6.1)]. As a precaution, assessment of orthostatic vital signs is recommended prior to initiation of Cycloset and periodically thereafter. During early treatment with Cycloset, patients should be advised to make slow postural changes and to avoid situations that could lead to serious injury if syncope was to occur. Use caution in patients taking anti-hypertensive medications.

Psychotic disorders

In patients with severe psychotic disorders, treatment with a dopamine receptor agonist such as Cycloset may exacerbate the disorder or may diminish the effectiveness of drugs used to treat the disorder. Therefore, the use of Cycloset in patients with severe psychotic disorders in not recommended.

Somnolence

Cycloset may cause somnolence. In a 52-week, randomized clinical trial, 4.3% of Cycloset treated-patients and 1.3% of placebo-treated patients reported somnolence as an adverse event. None of these events were reported as serious and the majority of patients reported resolution of somnolence over time. Patients should be made aware of this potential side effect, particularly when initiating therapy with Cycloset. Patients experiencing somnolence should refrain from driving or operating heavy machinery.

Interaction with dopamine receptor antagonists

Dopamine receptor antagonists, including neuroleptic agents that have dopamine D2 receptor antagonist properties (e.g. Clozapine, Olanzapine, Ziprasidone), may reduce the effectiveness of Cycloset and Cycloset may reduce the effectiveness of these agents. Cycloset has not been studied in patients taking neuroleptic drugs. The concomitant use of Cycloset and dopamine receptor antagonists, including neuroleptic drugs, is not recommended.

Other dopamine receptor agonists

Other dopamine receptor agonists are indicated for the treatment of Parkinson's disease, hyperproloactinemia, restless leg syndrome, acromegaly, and other disorders. The effectiveness and safety of Cycloset in patients who are already taking one of these other dopamine receptor agonists is unknown. Concomitant use is not recommended.

. Macrovascular outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Cycloset or any other anti-diabetic drug. In a 52-week, randomized clinical trial, Cycloset use was not associated with an increased risk for adverse cardiovascular events [See Adverse Reactions (6.1)].

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

In the pooled Cycloset phase 3 clinical trials (Cycloset N = 2298; placebo N = 1266), adverse events leading to discontinuation occurred in 539 (24%) Cycloset-treated patients and 118 (9%) placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea.

The Cycloset safety trial was a 52-week, placebo-controlled study that included patients treated only with diet therapy or with other anti-diabetic medications. A total of 3,070 patients were randomized to Cycloset (titrated to 1.6 to 4.8 mg daily, as tolerated) or placebo. The study population had a mean baseline age of 60 years (range 27-80) and 33% were 65 years of age or older. Approximately 43% of the patients were female, 68% were Caucasian, 17% were Black, 13% were Hispanic, and 1% were Asian. The mean baseline body mass index was 32 kg/m2. The mean duration of diabetes at baseline was 8 years and the mean baseline HbA1c was 7.0% with a mean baseline fasting plasma glucose of 142 mg/dL. At baseline, 12% of patients were treated with diet only, 40% were treated with one oral anti-diabetic agent, 33% were treated with two oral anti-diabetic agents, and 16% were treated with insulin alone or insulin in combination with an oral anti-diabetic agent. At baseline, 76% of patients reported a history of hypercholesterolemia, 75% reported a history of hypertension, 11% reported a history of revascularization surgery, 10% reported a history of myocardial infarction, 10% reported a history of angina, and 5% reported a history of stroke. Forty-seven percent of the Cycloset-treated patients and 32% of the placebo-treated patients prematurely discontinued treatment. Adverse events leading to discontinuation of study drug occurred among 24% of the Cycloset-treated patients and 15% of the placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea.

Table 1 summarizes the adverse events reported in ≥5% of patients treated with Cycloset in the phase 3 clinical trials regardless of investigator assessment of causality. The most commonly reported adverse events (nausea, fatigue, vomiting, headache, dizziness) lasted a median of 14 days and were more likely to occur during the initial titration of Cycloset. None of the reports of nausea or vomiting were described as serious. There were no differences in the pattern of common adverse events across race groups or age groups (<65 years old vs. >65 years old). In the 52-week Cycloset safety trial, 11.5% of Cycloset-treated women compared to 3.6% of placebo-treated women reported vomiting. In this same trial, 5.4% of Cycloset-treated men compared to 2.8% of placebo-treated men reported vomiting.

Table 1 Adverse Events Reported in Phase 3 Clinical Trials of Cycloset (≥5% of Patients and Numerically More Frequent in Cycloset-Treated Patients than in Placebo-Treated Patients, Regardless of Investigator Assessment of Causality†)

†All randomized subjects receiving at least one dose of study drug
‡ The Safety Trial enrolled patients treated with diet or no more than 2 anti-diabetic medications (metformin, insulin secretagogues such as a sulfonylurea, thiazolidinediones, alpha glucosidase inhibitors, and/or Insulin)
Monotherapy	Cycloset 1.6 mg – 4.8 mg N (%)	Placebo N (%)
N = 159	N = 80	N = 79
Nausea	26 (32.5)	6 (7.6)
Rhinitis	11 (13.8)	3 (3.8)
Headache	10 (12.5)	7 (8.9)
Asthenia	10 (12.5)	5 (6.3)
Dizziness	10 (12.5)	6 (7.6)
Constipation	9 (11.3)	3 (3.8)
Sinusitis	8 (10.0)	2 (2.5)
Diarrhea	7 (8.8)	4 (5.1)
Amblyopia	6 (7.5)	1 (1.3)
Dyspepsia	6 (7.5)	2 (2.5)
Vomiting	5 (6.3)	1 (1.3)
Infection	5 (6.3)	4 (5.1)
Anorexia	4 (5.0)	1 (1.3)
Adjunct to Sulfonylurea (2 pooled 24 week studies)
N = 494	N = 244	N = 250
Nausea	62 (25.4)	12 (4.8)
Asthenia	46 (18.9)	20 (8.0)
Headache	41 (16.8)	40 (16.0)
Flu syndrome	23 (9.4)	19 (7.6)
Constipation	24 (9.8)	11 (4.4)
Cold	20 (8.2)	20 (8.0)
Dizziness	29 (11.9)	14 (5.6)
Rhinitis	26 (10.7)	12 (4.8)
Sinusitis	18 (7.4)	16 (6.4)
Somnolence	16 (6.6)	5 (2.0)
Vomiting	13 (5.3)	8 (3.2)
Amblyopia	13 (5.3)	6 (2.4)
52-Week Safety Trial‡
N=3070	N = 2054	N = 1016
Nausea	661 (32.2)	77 (7.6)
Dizziness	303 (14.8)	93 (9.2)
Fatigue	285 (13.9)	68 (6.7)
Headache	235 (11.4)	84 (8.3)
Vomiting	167 (8.1)	32 (3.1)
Diarrhea	167 (8.1)	81 (8.0)
Constipation	119 (5.8)	52 (5.1)

Hypoglycemia

In the monotherapy trial, hypoglycemia was reported in 2 Cycloset-treated patients (3.7%) and 1 placebo-treated patient (1.3%). In the add-on to sulfonylurea trials, the incidence of hypoglycemia was 8.6% among the Cycloset-treated patients and 5.2% among the placebo-treated patients. In the Cycloset safety trial, hypoglycemia was defined as any of the following: 1) symptoms suggestive of hypoglycemia that promptly resolved with appropriate intervention, 2) symptoms with a measured glucose <60 mg/dL or 3) measured glucose below 49 mg/dL regardless of symptoms. In the 52-week safety trial, the incidence of hypoglycemia was 6.9% among the Cycloset-treated patients and 5.3% among the placebo-treated patients. In the safety trial, severe hypoglycemia was defined as an inability to self-treat neurological symptoms consistent with hypoglycemia that occurred in the setting of a measured blood glucose < 50 mg/dl (or evidence of prompt resolution of these symptoms with administration of oral carbohydrates, subcutaneous glucagon, or intravenous glucose if blood glucose was not measured). In this trial, severe hypoglycemia was reported among 0.5% of Cycloset-treated patients and 1% of placebo-treated patients.

Syncope

In combined phase 2 and 3 clinical trials, syncope was reported in 1.4% of the 2,500 Cycloset-treated patients and 0.6% of the 1,454 placebo-treated patients. Among the 3,070 patients studied in the 52-week safety trial, 33 Cycloset-treated patients (1.6%) and 7 placebo-treated patients (0.7%) reported an adverse event of syncope. The cause of syncope is not known in all cases [See Warnings and Precautions (5.1)]. In this trial, electrocardiograms were not available at the time of these events, but an assessment of routine electrocardiograms obtained during the course of the trial did not identify arrhythmias or QTc interval prolongation among the Cycloset-treated patients reporting syncope.

Central Nervous System

In the 52-week safety trial, somnolence and hypoesthesia were the only adverse events within the nervous system organ class that were reported at a rate of < 5% and ≥ 1% and that occurred at a numerically greater frequency among Cycloset-treated patients (Cycloset 4.3% vs. Placebo 1.3% for somnolence; Cycloset 1.4% vs. Placebo 1.1% for hypoesthesia).

Serious Adverse Events and Cardiovascular Safety

The primary endpoint of the 52-week safety trial was the occurrence of all serious adverse events. A secondary endpoint was the occurrence of the composite of myocardial infarction, stroke, coronary revascularization, hospitalization for angina, and hospitalization for congestive heart failure.

All serious adverse events and cardiovascular endpoints were adjudicated by an independent event adjudication committee. Serious adverse events occurred in 176/2054 (8.5%) Cycloset-treated patients and 98/1016 (9.6%) placebo-treated patients. The hazard ratio comparing Cycloset to placebo for the time to first occurrence of a serious adverse event was 1.02 (upper bound of one-sided 96% confidence interval, 1.27). None of the serious adverse events grouped by System-Organ-Class occurred more than 0.3 percentage points higher with Cycloset than with placebo. The composite cardiovascular endpoint occurred in 31 (1.5%) Cycloset-treated patients and 30 (3.0%) placebo-treated patients. The hazard ratio comparing Cycloset to placebo for the time-to-first occurrence of the prespecified composite cardiovascular endpoint was 0.58 (two-sided 95% confidence interval, 0.35 – 0.96). Therefore, the incidence of this composite endpoint was not increased with Cycloset relative to placebo.

Postmarketing Experience

The active agent in Cycloset (bromocriptine mesylate) has been used in other formulations and often multiple times per day to treat hyperprolactinemia, acromegaly, and Parkinson's disease. The following adverse reactions have been identified during postapproval use of bromocriptine mesylate for these indications, generally at doses higher than those approved for the treatment of type 2 diabetes. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hallucinations

Hallucinations and mental confusion including delusions have been reported with bromocriptine. To date, there have been no reported cases of hallucinations or delusions among Cycloset-treated patients (n= 2500) in combined Phase 2 and 3 clinical trials of Cycloset.

Fibrotic - Related Complications

Fibrotic complications, including cases of retroperitoneal fibrosis, pulmonary fibrosis, pleural effusion, pleural thickening, pericarditis and pericardial effusions have been reported. These complications do not always resolve when bromocriptine is discontinued. Among several studies investigating a possible relation between bromocriptine exposure and cardiac valvulopathy, some events of cardiac valvulopathy have been reported, but no definitive association between bromocriptine mesylate use and clinically significant (moderate to severe) cardiac valvulopathy could be concluded.

To date, there have been no reported cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis or pericardial effusions among the Cycloset–treated patients (n=2500) in combined Phase 2 and 3 controlled clinical trials of Cycloset. There was one unconfirmed case (0.04% event rate) of an adverse event of pulmonary fibrosis classified as non-serious in a Cycloset-treated patient.

No cases of cardiac valvulopathy have been reported in any of the clinical studies to date with Cycloset.

Psychotic and Psychiatric Disorders

Psychotic disorders have been reported with bromocriptine. Additionally, pathological gambling has been reported with bromocriptine used to treat patients with Parkinson's disease. To date, there have been no reported cases of psychoses or pathological gambling among the Cycloset-treated patients (N=2500) in combined Phase 2 and 3 controlled clinical trials of Cycloset.

Stroke

The indication for use of bromocriptine for inhibition of postpartum lactation was withdrawn based on postmarketing reports of stroke. Causality of bromocriptine use and the occurrence of stroke in this patient population has not been proven. Based on the Cycloset clinical trials, there is no evidence of increased risk for stroke when Cycloset is used to treat type 2 diabetes.

Neuroleptic - like malignant syndrome

A neuroleptic-like malignant syndrome (manifested by high fever and increase in creatinine phosphokinase) has been reported upon cessation of bromocriptine treatment in patients with advanced Parkinson's disease or patients with secondary Parkinsonism. To date, there have been no reported cases of neuroleptic-like malignant syndrome in combined Phase 2 and 3 controlled clinical trials of Cycloset, including the Safety Trial (N=2500). In the Cycloset Safety Trial, there were no reports of neuroleptic-like malignant syndrome during the 30 days of follow-up after cessation of Cycloset (N = 2054).

Drug Interactions

• The active ingredient in Cycloset, bromocriptine mesylate, is highly bound to serum proteins. Therefore, Cycloset may increase the unbound fraction of other concomitantly used highly protein-bound therapies (e.g., salicylates, sulfonamides, chloramphenicol and probenecid), which may alter their effectiveness and risk for side effects.


• Cycloset is a dopamine receptor agonist. Concomitant use of dopamine receptor antagonists, such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes), or metoclopramide may diminish the effectiveness of Cycloset and Cycloset may diminish the effectiveness of these other therapies. The concurrent use of Cycloset with these agents has not been studied in clinical trials and is not recommended [see Warning and Precautions 5.4].


• Cycloset in combination with ergot-related drugs may cause an increase in the occurrence of ergot-related side effects such as nausea, vomiting, and fatigue, and may also reduce the effectiveness of these ergot therapies when used to treat migraine. The concurrent use of these ergot agents within 6 hours of Cycloset dosing is not recommended.


• Cycloset is extensively metabolized by the liver via CYP3A4. Therefore, potent inhibitors or inducers of CYP3A4 may increase or reduce the circulating levels of Cycloset, respectively. Use caution when co-administering drugs that are strong inhibitors, inducers, or substrates of CYP3A4 (e.g., azole antimycotics, HIV protease inhibitors) [See Phamacokinetics (12.3)].


• There are postmarketing reports of hypertension and tachycardia when bromocriptine was co-administered with sympathomimetic drugs (e.g. phenylpropanolamine and isometheptene) in postpartum women. There are limited clinical trial data supporting the safety of co-administering sympathomimetic drugs and Cycloset for more than 10 days. Therefore, concomitant use of these agents with Cyclosetfor more than 10 days duration is not recommended. Also, there are limited clinical trial data supporting the safety of selective 5-hydroxytryptamine1B (5-HT1B) agonists (e.g. sumatriptan) used concurrently with Cycloset and the concomitant use of these agents with Cycloset should be avoided.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B:

Two strains of pregnant rats were dosed orally with 3, 10, and 30 mg/kg/day (up to 72 times the human 4.8 mg daily dose, based on mg/m2 comparison) from gestation day 6-15 and with a single dose of 10 mg/kg on gestation day 5. Implantation was inhibited at 10 and 30 mg/kg (24 and 72 times the human 4.8 mg daily dose, based on mg/m2 comparison). When rats were dosed with 3, 10, and 30 mg/kg/day from gestation day 8-15 there was an increase in resorptions at 10 and 30 mg/kg. These effects were probably due to the dependence of implantation and the maintenance of gestation on prolactin in the rat and are not relevant for humans in which these events are not dependent on prolactin but on luteinizing hormone. There was no evidence of teratogenic effects in the rat.

In a small study in macaque monkeys given oral doses of 2 mg/kg/day (10 times the human 4.8 mg daily dose, based on mg/m2 comparison) during organogenesis no embryotoxic or teratologic effects were observed.

When male rats given oral doses of 2, 10 or 50 mg/kg/day (up to 120 times the human 4.8 mg daily dose, based on mg/m2 comparison) were mated with untreated females, there was a slight increase in pup loss in the 10 and 50 mg/kg/day groups (24-120 times the human 4.8 mg daily dose, based on mg/m2 comparison).

In two strains of pregnant rabbits treated from gestation day 6-18 with oral doses of 3, 10, 30, 100, and 300 mg/kg/day (up to 1400 times the human 4.8 mg daily dose, based on mg/m2 comparison) there was maternal toxicity and embryolethality at doses ≥10 mg/kg/day (48 times the human 4.8 mg daily dose, based on mg/m2 comparison). Low incidences of fetal abnormalities were observed at maternally toxic doses of 100-300 mg/kg/day (480-1400 times the human 4.8 mg daily dose, based on mg/m2 comparison). There were no treatment-related fetal abnormalities at doses ≤30 mg/kg/day (140 times the human 4.8 mg daily dose, based on mg/m2 comparison). Implantation was not affected in rabbits treated from gestation day 1-6 with oral doses of 100-300 mg/kg/day (480-1400 times the human 4.8 mg daily dose, based on mg/m2 comparison).

Studies in pregnant women have not shown that bromocriptine increases the risk of abnormalities when administered during pregnancy. Information concerning 1,276 pregnancies in women taking bromocriptine has been collected. In the majority of cases, bromocriptine was discontinued within the first 8 weeks of pregnancy (mean 29 days); however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg). Of these 1,276 pregnancies, there were 1,088 full-term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Twelve extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11-25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin. Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 10-15% in the general population. The incidence of birth defects in the general population ranges from 2% to 4.5%. The incidence of birth defects in 1,109 live births from patients receiving bromocriptine was 3.3%. There is no suggestion that bromocriptine contributed to the type or incidence of birth defects in this group of infants.

A review of 4 different multicenter surveillance programs analyzed 2,351 pregnancies of 2,185 women treated with bromocriptine. In 583 children born of these women and followed for a minimum of 3-12 months, there was no suggestion of any adverse effect of intra-uterine exposure to bromocriptine on post-natal development. Most (≥75%) women had taken bromocriptine for 2-8 weeks and at 5-10 mg per day. Among 86 women having 93 pregnancies and treated with bromocriptine throughout pregnancy or from week 30 of pregnancy onwards (mostly for treatment of prolactinoma), there was only 1 spontaneous abortion. Similar results have been obtained in a Japanese hospital survey of 442 children born to 434 patients treated with bromocriptine during pregnancy and followed for at least one year.

Because the studies in humans cannot rule out the possibility of harm, Cycloset should be used during pregnancy only if clearly needed.

Nursing Mothers

Cycloset is contraindicated in women who are nursing their children. Cycloset contains bromocriptine which inhibits lactation. The indication for use of bromocriptine for inhibition of postpartum lactation was withdrawn based on postmarketing reports of stroke in this setting [See Contraindications (4) and Adverse Reactions (6.2)].

Pediatric Use

The safety and effectiveness of Cycloset in pediatric patients have not been established.

Geriatric Use

In the two clinical trials of Cycloset add-on to sulfonylurea therapy and in the monotherapy trial, a total of 54 patients randomized to Cycloset were ≥65 years old. In the 52-week safety trial, 601 of the 2,054 Cycloset-treated patients (29%) were ≥65 years old. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. [See Clinical Studies (14)].

Overdosage

With another formulation of bromocriptine mesylate, the most commonly reported signs and symptoms associated with acute overdose were nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The lethal dose has not been established.

Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is essential. Hypotension should be treated by placing the patient in the Trendelenburg position and administering intravenous fluids. If satisfactory relief of hypotension cannot be achieved by using the above measures to their fullest extent, vasopressors should be considered.

Cycloset Description

Cycloset Tablets contain bromocriptine mesylate, a dopamine receptor agonist. Bromocriptine mesylate is chemically designated [Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-, monomethanesulfonate (salt), (5'α)-]. Cycloset is a single enantiomer with absolute configuration 5R, 8R, 2'R, 5'S, 11'S, 12'S.

The structural formula of bromocriptine is shown below:

Bromocriptine mesylate is a white or slightly colored fine crystalline powder with a molecular formula of C32H40BrN5O5∙CH4SO3 and a molecular weight of 750.72. Cycloset tablets contain bromocriptine mesylate USP in an amount equivalent to 0.8 of bromocriptine. Each tablet contains the following inactive ingredients: lactose, corn starch, magnesium stearate, colloidal silicon dioxide, and citric acid.

Cycloset - Clinical Pharmacology

Mechanism of Action

Cycloset contains bromocriptine mesylate, an ergot derivative that is a dopamine receptor agonist. The mechanism by which Cycloset improves glycemic control is unknown. Morning administration of Cycloset improves glycemic control in patients with type 2 diabetes without increasing plasma insulin concentrations.

Once daily morning administration of Cycloset to humans increases circulating levels of bromocriptine, a dopamine receptor agonist, for 4-5 hours after administration.

Pharmacodynamics

Postprandial Glucose and Insulin Response to a Meal

Patients with type 2 diabetes and inadequate glycemic control on diet alone were randomized to Cycloset or placebo in a 24-week monotherapy clinical trial. At baseline and study end, plasma samples for insulin and glucose were obtained before and 1 hour, and 2 hours after standardized meals for breakfast, lunch, and dinner. In this trial, once-daily (8 a.m.) Cycloset improved post-prandial glucose without increasing plasma insulin concentrations.

Pharmacokinetics

Absorption and Bioavailability

When administered orally, approximately 65-95% of the Cycloset dose of bromocriptine mesylate is absorbed. Due to extensive hepatic extraction and first-pass metabolism, approximately 7% of the dose reaches the systemic circulation. Under fasting conditions the time to maximum plasma concentration is 53 minutes. In contrast, following a standard high-fat meal, the time to maximum plasma concentration is increased to approximately 90-120 minutes. Also, the relative bioavailability of Cycloset is increased under fed as compared to fasting conditions by an average of approximately 55-65% (increase in AUCinf).

Distribution

Bromocriptine is 90-96% bound to plasma proteins. The volume of distribution is approximately 61 L.

Metabolism

Bromocriptine mesylate is extensively metabolized in the gastrointestinal tract and liver. Metabolism by CYP3A4 is the major metabolic pathway. Most of the absorbed dose (approximately 93%) undergoes first-pass metabolism. The remaining 7% reaches the systemic circulation.

Excretion

The major route of excretion of bromocriptine is in the bile with the remaining approximately 2-6% of an oral dose excreted via the urine. The elimination half-life is approximately 6 hours. Prior consumption of a standard high-fat meal has little to no effect on the elimination half-life of Cycloset.

Specific Populations

Renal Impairment

No pharmacokinetic studies have been conducted in patients with renal impairment. Although the kidney is a minor pathway for elimination of Cycloset, caution should be used in patients with renal impairment.

Hepatic Impairment

No pharmacokinetic studies have been conducted in patients with hepatic impairment. Because Cycloset is predominantly metabolized by the liver, caution should be used in patients with hepatic impairment.

Gender

The plasma exposure of Cycloset is increased 18-30% in females compared to males.

Geriatric

No pharmacokinetic studies have been conducted in geriatric subjects.

Pediatric

Studies characterizing the pharmacokinetics of Cycloset in pediatric patients have not been performed.

Race

Studies characterizing the pharmacokinetics of Cycloset among different ethnic groups have not been performed.

In Vitro Assessment of Drug Interactions

Results from in vitro studies demonstrate that CYP3A4 is the major enzyme responsible for the metabolism of bromocriptine. Bromocriptine is a competitive inhibitor of CYP3A4. The inhibitory potency for CYP3A4 is approximately 10,000-fold higher than the maximum plasma levels reached in vivo (Cmax of approximately 80-125 pg/mL) following a 4.8 mg oral dose of Cycloset.

Agents inducing CYP3A4 activity such as rifampin or dexamethasone would be expected to decrease Cycloset plasma levels. There was no significant in vitro inhibition of other major CYP450 enzymes (1A2, 2C9/19, 2D6) by bromocriptine.

In Vivo Assessment of Drug Interactions

The concomitant use of macrolide antibiotics such as erythromycin (250 mg four times a day), a known inhibitor of CYP3A4, along with bromocriptine (5 mg) was shown to increase the AUC (2.8 fold) and Cmax (4.6 fold) of bromocriptine. Therefore, use caution when co-administering drugs that are strong inhibitors or substrates of this enzyme, such as azole antimycotics and HIV protease inhibitors.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 74-week dietary study in mice at doses up to 50 mg/kg/day (56 times the human 4.8 mg daily dose, based on mg/m2 comparison) there was no evidence of tumorigenicity.

In a 100-week dietary carcinogenicity study in rats at doses of 1.8, 9.9 and 44.5 mg/kg/day (up to 106 times the human 4.8 mg daily dose, based on mg/m2 comparison) there was a significant increase in the incidence of malignant uterine neoplasms in the mid- and high dose groups (24-106 times the human 4.8 mg daily dose, based on mg/m2 comparison). The increase in uterine neoplasms was probably due to the inhibition of prolactin-stimulated progesterone secretion resulting in estrogen domination and endometrial stimulation in the aging rat. Because prolactin does not play a role in human progesterone production this finding is unlikely to be clinically relevant.

Mutagenicity

Bromocriptine was not mutagenic in the in vitro Ames bacterial mutation assay, the V79 Chinese hamster fibroblast mutagenity test, the in vivo bone marrow micronucleus test in mice and the in vivo Chinese hamster bone marrow chromosomal aberration test.

Impairment of Fertility

In female rats treated with oral doses of 1 and 3 mg/kg (2 to 7 times the human 4.8 mg daily dose, based on mg/m2 comparison) from 2 weeks prior to mating through 2 weeks post mating or throughout lactation there was no effect on fertility. Postnatal pup weight gain was reduced dose-dependently in treated groups probably due to lactation inhibition.

In male rats treated with oral doses of 2, 10, and 50 mg/kg/day (up to 120 times the human 4.8 mg daily dose, based on mg/m2 comparison) there was no effect on mating or fertility.

Clinical Studies

A total of 3,723 patients with type 2 diabetes were randomized across 4 double-blind, placebo-controlled clinical trials conducted to evaluate the safety and glycemic efficacy of Cycloset. In the pooled 24-week monotherapy trial and the two 24-week add-on to sulfonylurea trials (N = 653), the mean age of the Cycloset-treated patients (N=324) was 55 years, 71% were male and 73% Caucasian. In the 52-week safety trial (N=3,070), the mean age for the entire study population was 60 years and 43% of patients were female, 68% were Caucasian, 17% were Black, 13% were Hispanic, and 1% were Asian.

In all 4 clinical trials, patients assigned to treatment with Cycloset received an initial dose of 0.8 mg, which was increased by 0.8 mg each week for 6 weeks (4.8 mg/day final dose) if no intolerance occurred or until the maximum tolerated dose ≥ 1.6 mg/day was reached. In patients with type 2 diabetes, treatment with Cycloset produced clinically significant improvements in HbA1c and postprandial glucose (PPG).

Monotherapy

A total of 159 overweight (body mass index ≥26.0 kg/m2 for males and ≥28.0 kg/m2 for females) adults with type 2 diabetes and inadequate glycemic control (HbA1c 7.5-11%) participated in a 24-week placebo-controlled monotherapy trial that evaluated the efficacy and safety of Cycloset as an adjunct to diet and exercise. Mean body weight at baseline was 93 kg in the Cycloset group and 96 kg in the placebo group. Mean HbA1c at baseline was 9.0% in the Cycloset group and 8.8% in the placebo group. Mean duration of diabetes at baseline was 5 years in the Cycloset group and 4 years in the placebo group. Of the 80 patients in the CYLCOSET group, 69% (N=55) achieved the maximum daily dose of 4.8 mg. Cycloset improved HbA1c and fasting plasma glucose compared to placebo (Table 2). Mean change from baseline in body weight was +0.2 kg in the Cycloset group (N=78) and +0.5 kg in the placebo group (N=77).

Table 2 Changes in Glycemic Parameters in a 24-Week Placebo –Controlled Study of Cycloset as Monotherapy in Patients with Type 2 Diabetes†

†intent to treat population with last observation carried forward
P-value calculated by ANOVA; *p=0.05, **p=0.005
	Cycloset N=80 (1.6 -4.8 MG)	Placebo N=79
HbA1C (%)	N = 74	N = 74
Baseline (mean)	9.0	8.8
Change from baseline (adj. mean)	-0.1	0.3
Difference from placebo (adj. mean)	-0.4*
Fasting Plasma Glucose (mg/dl)	N = 76	N = 75
Baseline (mean)	215	205
Change from baseline (adj. mean)	0	23
Difference from placebo (adj. mean)	-23**

Combination Therapy

Cycloset add-on to sulfonylurea therapy

Patients with type 2 diabetes and inadequate glycemic control (HbA1c 7.8-12.5%) on sulfonylurea therapy (mean HbA1c 9.4%) participated in Study L, a 24-week, randomized, double-blind, placebo-controlled trial that evaluated the safety and glycemic efficacy of Cycloset when added to stable sulfonylurea therapy. The mean duration of diabetes was 6 years in the Cycloset group and 8 years in the placebo group. The range of body mass index was 26-40 kg/m2 for men and 28-40 kg/m2 for women, with a mean of 32 kg/m2 in both treatment groups. Of the 122 patients in the Cycloset group, 83 (68%) achieved the maximum dose of study drug. The mean change from baseline in body weight was +0.9 kg in the Cycloset group and +0.5 kg in the placebo group.

In another similarly designed trial, Study K, patients with type 2 diabetes and inadequate glycemic control (HbA1c 7.8-12.5 %) on stable sulfonylurea therapy were randomized to add-on therapy with either Cycloset (N = 122) or placebo (N = 123). The range of body mass index was 26-40 kg/m2 for men and 28-40 kg/m2 for women, with a mean of 32 kg/m2 in the Cycloset group and 33 kg/m2 in the placebo group. Of the 122 patients in the Cycloset group, 91 (75%) achieved the maximum dose of study drug. Mean change from baseline in body weight was +1.4 kg in the Cycloset group and +0.5 kg in the placebo group. Cycloset improved HbA1c and fasting blood glucose concentrations compared to placebo

Cyanocobalamin/Folic Acid/Iron

Pronunciation: SYE-an-oh-koe-BAL-a-min/FOE-lik AS-id/EYE-urn
Generic Name: Cyanocobalamin/Folic Acid/Iron
Brand Name: Examples include BiferaRx and Ferrex 150 Forte

Accidental overdose of products that contain iron is a leading cause of fatal poisoning in children younger than 6 years old. Keep this and all medicines out of the reach of children. In case of accidental ingestion, call the poison control center or a doctor at once.

Cyanocobalamin/Folic Acid/Iron is used for:

Preventing and treating certain types of anemia (eg, caused by low blood iron levels, poor nutrition). It may also be used for other conditions as determined by your doctor.

Cyanocobalamin/Folic Acid/Iron is a vitamin, folic acid, and iron combination. It works by providing vitamins, folic acid, and iron to the body.

Do NOT use Cyanocobalamin/Folic Acid/Iron if:

• you are allergic to any ingredient in Cyanocobalamin/Folic Acid/Iron


• you have certain iron metabolism problems (eg, hemosiderosis, hemochromatosis) or you have high levels of iron in your blood

Contact your doctor or health care provider right away if any of these apply to you.

Before using Cyanocobalamin/Folic Acid/Iron:

Some medical conditions may interact with Cyanocobalamin/Folic Acid/Iron. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have bowel problems (eg, colitis, Chron disease, diverticulitis), certain blood disorders (eg, hemolytic or pernicious anemia, porphyria cutanea tarda, thalassemia), or a peptic ulcer


• if you have had multiple blood transfusions

Some MEDICINES MAY INTERACT with Cyanocobalamin/Folic Acid/Iron. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Fluorouracil because the risk of its side effects may be increased by Cyanocobalamin/Folic Acid/Iron


• Bisphosphonates (eg, alendronate), cephalosporins (eg, cefdinir), hydantoins (eg, phenytoin), levodopa, methyldopa, mycophenolate, penicillamine, quinolones (eg, ciprofloxacin, levofloxacin), tetracyclines (eg, doxycycline), or thyroid hormones (eg, levothyroxine) because their effectiveness may be decreased by Cyanocobalamin/Folic Acid/Iron

This may not be a complete list of all interactions that may occur. Ask your health care provider if Cyanocobalamin/Folic Acid/Iron may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Cyanocobalamin/Folic Acid/Iron:

Use Cyanocobalamin/Folic Acid/Iron as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Cyanocobalamin/Folic Acid/Iron by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Do not take an antacid within 1 hour before or 2 hours after you take Cyanocobalamin/Folic Acid/Iron.


• Avoid taking Cyanocobalamin/Folic Acid/Iron with dairy products; they may interfere with the absorption of the iron in Cyanocobalamin/Folic Acid/Iron.


• If you also take a bisphosphonate (eg, alendronate), a cephalosporin (eg, cefdinir), eltrombopag, levodopa, methyldopa, penicillamine, a quinolone (eg, ciprofloxacin), or a tetracycline (eg, doxycycline), ask your doctor or pharmacist how to take it with Cyanocobalamin/Folic Acid/Iron.


• If you miss a dose of Cyanocobalamin/Folic Acid/Iron, 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 Cyanocobalamin/Folic Acid/Iron.

Important safety information:

• Do NOT take more than the recommended dose without checking with your doctor.


• Do not take large doses of vitamins (megadoses or megavitamin therapy) while you use Cyanocobalamin/Folic Acid/Iron unless your doctor tells you to.


• Cyanocobalamin/Folic Acid/Iron has folic acid and iron in it. Before you start any new medicine, check the label to see if it also has folic acid or iron in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Cyanocobalamin/Folic Acid/Iron may discolor the stools. This is normal and not a cause for concern.


• Cyanocobalamin/Folic Acid/Iron has iron in it. Iron overdose is a leading cause of fatal poisoning in children younger than 6 years of age. In case of an overdose, call a doctor or poison control center right away.


• Cyanocobalamin/Folic Acid/Iron may interfere with certain lab tests, including tests used to check for blood in the stool. Be sure your doctor and lab personnel know you are taking Cyanocobalamin/Folic Acid/Iron.


• Lab tests, including hematocrit, hemoglobin levels, and blood iron levels, may be performed while you use Cyanocobalamin/Folic Acid/Iron. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Cyanocobalamin/Folic Acid/Iron should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Cyanocobalamin/Folic Acid/Iron while you are pregnant. Cyanocobalamin/Folic Acid/Iron is found in breast milk. If you are or will be breast-feeding while you use Cyanocobalamin/Folic Acid/Iron, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Cyanocobalamin/Folic Acid/Iron:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; dark or green stools; diarrhea; nausea; stomach pain; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry, or bloody stools; severe or persistent nausea, vomiting, or stomach pain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include black, tarry, or bloody stools; blue or unusually pale skin; drowsiness or dizziness; fast heartbeat; increased thirst or urination; seizures; severe or persistent nausea, vomiting, diarrhea, or stomach pain; sluggishness; vomiting blood; weakness.

Proper storage of Cyanocobalamin/Folic Acid/Iron:

Store Cyanocobalamin/Folic Acid/Iron at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Cyanocobalamin/Folic Acid/Iron out of the reach of children and away from pets.

General information:

• If you have any questions about Cyanocobalamin/Folic Acid/Iron, please talk with your doctor, pharmacist, or other health care provider.


• Cyanocobalamin/Folic Acid/Iron is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Cyanocobalamin/Folic Acid/Iron. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Cyanocobalamin/Folic Acid/Iron resources

• Cyanocobalamin/Folic Acid/Iron Use in Pregnancy & Breastfeeding
• Drug Images
• Cyanocobalamin/Folic Acid/Iron Drug Interactions
• Cyanocobalamin/Folic Acid/Iron Support Group
• 11 Reviews for Cyanocobalamin/Folic Acid/Iron - Add your own review/rating

Compare Cyanocobalamin/Folic Acid/Iron with other medications

• Anemia
• Vitamin/Mineral Supplementation and Deficiency

cyclandelate

Generic Name: cyclandelate (sye KLAN de late)

Brand Names: Cyclospasmol

What is cyclandelate?

Cyclandelate is in a class of drugs called vasodilators. Cyclandelate relaxes veins and arteries, which makes them wider and allows blood to pass through them more easily.

These actions may help treat the symptoms of conditions such as leg cramps, arteriosclerosis (hardening of the arteries), Raynaud's phenomenon, and other conditions that involve poor blood flow in your veins and arteries.

Cyclandelate is not commercially available in the United States.

Cyclandelate may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about cyclandelate?

Cyclandelate is not commercially available in the United States.

Take cyclandelate with food or an antacid to lessen stomach discomfort.

What should I discuss with my healthcare provider before taking cyclandelate?

Before taking this medication, tell your doctor if you have

• 
  

  serious coronary artery disease;

  
  


• 
  

  peripheral or cerebral vascular disease;

  
  


• 
  

  glaucoma, or

  
  


• 
  

  bleeding or blood problems.

  
  

The safety of cyclandelate for use by pregnant or nursing women has not been established. Do not take cyclandelate without first talking to your doctor if you are pregnant or are breast-feeding a baby.

How should I take cyclandelate?

Take cyclandelate exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water. Take cyclandelate with food or an antacid to lessen stomach discomfort. Cyclandelate is usually taken two to four times a day, before meals and at bedtime. Follow your doctor's instructions. Store cyclandelate at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and take only your next regularly scheduled dose. Do not take a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a cyclandelate overdose include lightheadedness, weakness, fainting, headache, and a faint heartbeat.

What should I avoid while taking cyclandelate?

There are no restrictions on foods, beverages, or activities during therapy with cyclandelate. Follow any special instructions you receive from your doctor.

Cyclandelate side effects

Stop taking cyclandelate and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives).

Other, less serious side effects may be more likely to occur. Continue to take cyclandelate and talk to your doctor if you experience

• 
  

  heartburn, stomach upset, or belching;

  
  


• 
  

  flushing;

  
  


• 
  

  headache;

  
  


• 
  

  a fast heartbeat; or

  
  


• 
  

  weakness.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect cyclandelate?

Drugs used to treat high blood pressure and other heart conditions may increase the effects of cyclandelate. Special monitoring may be necessary.

Drugs other than those listed here may also interact with cyclandelate or affect your condition. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines.

More cyclandelate resources

• Drug Images
• Cyclandelate Drug Interactions
• Cyclandelate Support Group
• 0 Reviews for Cyclandelate - Add your own review/rating

• cyclandelate Advanced Consumer (Micromedex) - Includes Dosage Information

Compare cyclandelate with other medications

• Nocturnal Leg Cramps
• Raynaud's Syndrome
• Renal Artery Atherosclerosis

Where can I get more information?

• Your pharmacist has additional information about cyclandelate written for health professionals that you may read.

What does my medication look like?

Cyclandelate was formerly available with a prescription under the brand names Cyclan and Cyclospasmol in 200 mg and 400 mg capsules. Cyclandelate was also formerly available in a generic tablet formulation. Ask your pharmacist any questions you have about this medication, especially if it is new to you.