Quetiapine Fumarate - Indications, Side effects, Dosage, and Administration

Introduction

Quetiapine Fumarate belongs to the dibenzothiazepine class. The salt is designated as 2-[2-(4-dibenzo [1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol fumarate. The dosage in the tablets is expressed in milligrams and not as salt. The molecular formula for Quetiapine Fumarate is C42H50N6O4S2•C4H4O4. The molecular weight of Quetiapine Fumarate is 883.11 g/mol. It is off-white in color and crystal in structure.

For Doctors:

Clinical Pharmacology:

Pharmacodynamics:

Quetiapine Fumarate is an antagonist of various receptors such as 5 HT1A (histamine), 5 HT2, D1 (dopamine), D2, alpha 1, and 2 adrenergic receptors. It does not possess an affinity for cholinergic and benzodiazepine receptors. The mechanism of action of Quetiapine Fumarate is unknown. However, the efficacy of the drug for treating bipolar disorder is mediated through dopamine and serotonin antagonists. The antagonism of Quetiapine Fumarate of H1 receptors (histamine) implies somnolence. In comparison, the antagonism for adrenergic receptors implies orthostatic hypotension.

Pharmacokinetics:

The pharmacokinetics of Quetiapine is determined by multiple dosing. It depends on the clinical dose range and accumulation of the drug. Elimination of the drug occurs through hepatic metabolism. It has a mean half-life of six hours. Steady-state concentration occurs within two days. It does not interfere with other drugs metabolized by cytochrome P450 enzymes.

Absorption:

Quetiapine Fumarate reaches a peak in the plasma after 1.5 hours of oral administration. There is 100 % bioavailability for tablets and solutions. The bioavailability of Quetiapine is affected by food intake. Cmax and AUC of the drug are 25% and 15%, respectively.

Distribution:

The distribution of Quetiapine is 10 L/kg. 83% of the drug bounds to plasma. It does not affect the distribution of other drugs like Warfarin or Diazepam in the albumin. Also, Warfarin or Diazepam does not interfere with Quetiapine distribution.

Metabolism and Elimination:

After oral administration of Quetiapine, 1% was excreted as an unchanged dose. It indicates the complete metabolization of Quetiapine. 73% and 20% of the drug is present in urine and feces, respectively. The metabolism occurs in the liver. The pathways include sulfoxidation and oxidation. The sulfoxide metabolite and oxide metabolites remain inactive. Cytochrome P450 3A4 metabolizes the Quetiapine, but the sulfoxide metabolite remains inactive.

Population Distribution:

Age: When nine elderly patients more than 65 years of age are compared with 12 young adults, the oral clearance decreases by 40%.

Gender: Quetiapine has no gender effect.

Race: Pharmacokinetics of Quetiapine does not affect race.

Smoking: Smoking tobacco has no significant impact on oral clearance of Quetiapine.

Renal Insufficiency: Renal impairment patients have 25% less clearance compared with other individuals. But the plasma level of Quetiapine in severely renal impaired patients is similar to normal individuals. Hence, alteration of the dose is not necessary.

Hepatic Insufficiency: Patients with hepatic impairment have 30% oral clearance. The AUC and Cmax raised thrice more than the normal individuals. The plasma level of Quetiapine is increased in patients with hepatic impairment. Hence, adjustment of drug dosage is compulsory.

Drug to Drug Interactions: Quetiapine and its nine metabolites have an inhibitory effect on cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4. Oral clearance is induced by cytochrome P450 3A4 inducer and Phenytoin. It is decreased by P450 3A4 inhibitor and Ketoconazole. It is not affected by Cimetidine. 750 mg/day does not affect the pharmacokinetics of drugs such as Antipyrine, Lithium, and Lorazepam.

What Are the Indications and Uses of Quetiapine Fumarate?

Bipolar Mania:

Quetiapine is usually preferred for acute episodes in patients with a maniac and bipolar type 1 disorder. It is used as monotherapy or combined with Lithium or Divalproex.

Efficacy of Quetiapine is proved in two three-week monotherapy clinical trials, and one three-week combined therapy in patients admitted for a week to treat maniac disorder. It is not evaluated after three weeks. So Quetiapine should not be used for extended periods. In case of using it, the physician should ensure the risks and benefits of the drug on the concerned person.

Schizophrenia:

Quetiapine is used for treating disorders like schizophrenia. It is determined for six weeks in patients with schizophrenia. They have controlled trials. Efficacy of Quetiapine is not evaluated for more than six weeks of administration. Physicians must re-evaluate the use and effectiveness of Quetiapine.

Contraindications:

Quetiapine is not recommended for patients with hypersensitivity to this drug.

Warnings:

Neuroleptic Malignant Syndrome (NMS):

The neuroleptic malignant syndrome is a fatal symptom associated with the long-term use of Quetiapine Fumarate. Though the symptom is rare, it is a serious condition. The clinical manifestations include high fever, muscle stiffness, poor mental status, irregular pulse rate, tachycardia, and diaphoresis. There is an increased creatine phosphokinase with acute renal failure. Patients with NMS have complications. During diagnosis, the cases were excluded based on other systemic illnesses like infection, pneumonia, and untreated extrapyramidal signs and symptoms. Differential diagnosis of NMS includes fever, stroke, anticholinergic toxicity, and pathology in the nervous tissues.

Management of NMS includes;

• Discontinuation of antipsychotic drugs.

• Medical monitoring.

• Intensive care for the affected patients.

• Management of serious medical conditions.

There are no specific regimens for NMS. For patients who need antipsychotic drug therapy after recovering from NMS, the case should be carefully monitored. The recurrence rate is high for such patients.

Tardive Dyskinesia:

The patient has involuntary movements. This condition is irreversible. It is more commonly seen in elderly patients than young adults. Females are more commonly affected. Prevalence is impossible to predict based on the given data. The major cause of dyskinesia is not known. Risk increases with the long-term use of the drug. It also depends on the dosage of the drug. Low doses with brief treatment periods can reduce the symptoms.

There is no specific treatment for tardive dyskinesia. Partial or complete recurrence is seen during withdrawal. The symptomatic suppression with the drug is not known. Based on this condition, Quetiapine is prescribed. Chronic treatment is given only to patients who suffer from long-term illness, respond well to antipsychotic treatment, and do not respond to alternative drugs. Patients under long-term treatment should be prescribed small doses for effective clinical response.

Hyperglycemia and Diabetes Mellitus:

Patients with ketoacidosis are associated with the use of Quetiapine. The use of atypical antipsychotic drugs with glucose abnormalities is seen in patients with diabetes mellitus and schizophrenia. The relationship between antipsychotic drugs and hyperglycemia is not understood. However, there is an increased risk of hyperglycemia in patients treated with Quetiapine. Patients with known diabetic conditions taking antipsychotic medications should be monitored carefully. This can control excess glucose levels. Risk factors of diabetes include obesity and family history. Such patients should obtain blood glucose levels before starting the antipsychotic therapy. After treatment, symptoms like polydipsia, polyuria, and polyphagia indicate hyperglycemia. Fasting blood glucose tests can be used for diagnosing hyperglycemia. The management of hyperglycemia includes the withdrawal of antipsychotic drugs, but a continuation of antidiabetic drugs is necessary.

What Are the General Precautions of Quetiapine Fumarate?

Orthostatic Hypotension: Quetiapine causes orthostatic hypotension, dizziness, and syncope during the dose-titration. It occurs due to its antagonistic effect against adrenergic receptors. Syncope occurred in 1% of patients treated with Quetiapine while 0% on placebo and 0.4% in controlled trials. Quetiapine administration should be cautious in patients with heart diseases like ischemia, myocardial infarction, valvular abnormalities, and heart failure. Patients with cerebrovascular disease are prone to hypotension when more than 25 mg dosage is administered twice a day. The previous dose can be appropriate if hypotension due to titration occurs.

Cataracts:

Animal studies proved the association between cataracts and Quetiapine. Changes in the lens are observed in patients administered with long-term Quetiapine. The possibility of modifications in the lens should not be ignored. Diagnosis should be prepared using slit lamp examination and other sensitive methods. It is indicated during treatment initiation or six months after treatment.

Seizures:

Patients treated with Quetiapine were noted with a 0.6 % seizure attack compared to 0.1% on placebo and 0.5% in controlled trials. Administration of Quetiapine in patients with seizures should be minimal as it results in Alzheimer's dementia. A reduced seizure threshold is observed in elderly patients more than 65 years of age.

Hypothyroidism:

A clinical trial with Quetiapine indicates decreased dosage in thyroxine T4 of 20% when compared with the higher end of therapeutic dosage. It is observed in the four weeks of initial treatment. The progress is monitored during chronic therapy. TSH (thyroid stimulating hormone) remains unchanged with the dosage. Discontinuation of Quetiapine is related to the reversible effects of free T4 irrespective of the treatment period. 0.4% of patients treated with Quetiapine experienced an increase in TSH during monotherapy. Some patients required thyroid treatment. Few studies were conducted to determine the effect of Lithium or Valproate with Quetiapine. 7% of patients had low free T4 levels.

Cholesterol and Triglyceride Elevations:

Quetiapine-treated patients have an increase of 11% and 17% in cholesterol and triglyceride, respectively. It decreases for placebo patients. Weight change is not related to the drug dosage.

Hyperprolactinemia:

The increase in prolactin levels was not determined in the clinical trials of Quetiapine. A study conducted on rats showed increased prolactin levels were associated with an increase in the abnormal growth of the mammary gland. A study conducted on tissue culture revealed that the majority of breast cancer cases were prolactin dependent. Few other symptoms include amenorrhea, gynecomastia, and impotence. But the prolactin level in serum is not determined. Epidemiologic studies did not show the association between chronic drug administration and tumors. Hence, it cannot be confirmed.

Transaminase Elevations:

Asymptomatic but transient rise of serum transaminase is observed. Patients with schizophrenia and bipolar mania were studied for three weeks to six weeks in controlled trials. They were noted with an elevation of three times normal in the serum transaminase level. An increase in hepatic enzyme activity was observed during the first three weeks of the drug administration.

Potential for Cognitive Impairment: Somnolence is observed after five days of Quetiapine administration. In the control group of schizophrenic patients, 18% of patients were observed with somnolence. In patients with bipolar disorder, 16% were observed with somnolence. Quetiapine creates impairment of motor skills and interferes with judgment and thinking skills. Hence patients should avoid riding motor vehicles or using heavy machines during the treatment phase.

Priapism: Before the introduction of Quetiapine in the market, there was a case of priapism. But the association between Quetiapine and priapism is not studied. Alpha-adrenergic receptors were proved to cause priapism. These patients require surgical management.

Body Temperature Regulation: Quetiapine disrupts body temperature. Patients taking Quetiapine will experience an increased body temperature. This is similar to heat produced during vigorous exercise, medication with anticholinergic activity, or dehydration.

Dysphagia: Esophageal dysfunction occurs due to long-term Quetiapine use. Elderly patients are more prone to aspiration pneumonia. It causes death with advanced Alzheimer's dementia. Quetiapine should be carefully administered in patients with an increased risk of aspiration pneumonia.

Suicide: The risk of attempting suicide is high in patients with bipolar disorder and schizophrenia. They are prescribed with a lower dose of Quetiapine.

Concomitant Illness: Patients with renal and hepatic illness should be carefully examined before the administration of Quetiapine. The risk of Quetiapine use in patients with myocardial infarction was not evaluated. This is an exclusion from pre-marketing studies. The risk of orthostatic hypotension should be monitored in patients with unstable heart disease.

Drug Interactions

Few drugs affect Quetiapine.

They are as follows;

• Phenytoin - Administering 100 mg of Phenytoin thrice daily with 250 mg of Quetiapine twice daily increased the oral clearance of Quetiapine by five times. Hence increased dose of Quetiapine is administered in patients with schizophrenia and taking Phenytoin and Quetiapine. Phenytoin can be replaced by Valproate.

• Divalproex - Administration of 500 mg of Divalproex twice daily with 150 mg of Quetiapine twice daily increases the plasma concentration of Quetiapine by 17%. It does not affect the absorption or clearance of Quetiapine.

• Thioridazine - Administration of 200 mg of Thioridazine with 300 mg of Quetiapine increases 65% oral clearance.

• Cimetidine - The patient taking multiple doses of Cimetidine 400 mg four times daily with Quetiapine 150 mg twice daily has decreased clearance by 20%.

• P450 3 A Inhibitors - Administration of Ketoconazole 200 mg once daily for four days decreases the clearance of Quetiapine by 84%. But it increases the plasma concentration of Quetiapine by more than 200 %. Ketoconazole is a potent inhibitor of cytochrome P450 3 A. Hence caution is taken before administration.

• Fluoxetine - Administration of 60 mg with 300 mg of Quetiapine twice daily did not affect the clearance.

• Imipramine - Administration of 75 mg twice daily with 300 mg of Quetiapine did not alter the pharmacokinetics.

• Haloperidol - Administration of 7.5 mg of Haloperidol with 300 mg of Quetiapine had no variations in the pharmacokinetics.

• Risperidone - Administration of 3 mg of Risperidone with 300 mg of Quetiapine did not affect the absorption and clearance.

Effect of Quetiapine on Other Drugs:

Lorazepam: 2 mg of Lorazepam reduced its clearance by 20% during the administration of 250 mg.

Divalproex: The absorption of Valproate has decreased by 12% during the administration of Divalproex 500 mg with Quetiapine 150 mg. But the oral clearance was not altered during the administration of Divalproex 500 mg with Quetiapine 150 mg.

Lithium: Administration of Quetiapine did not affect the pharmacological effect of 250 mg of Lithium administration.

Antipyrine: Administration of 750 mg of Quetiapine to patients with psychotic disorders did not affect the metabolism and excretion of antipyrine metabolites. This indicates that Quetiapine does not affect the cytochrome P450 metabolism.

Carcinogenesis: Studies were conducted on rats to determine carcinogenesis in rats. They were administered with 20 mg, 75 mg, 250 mg, and 750 mg/kg. These doses were equivalent to 0.1, 0.5, 1.5, and 4.5 times in human dosage. It resulted in thyroid follicular adenomas in male rats. It is due to the chronic stimulation of TSH (thyroid stimulating hormone). Mammary gland adenocarcinomas are found in female rats. Antipsychotic drugs were proven to elevate the level of prolactin. The serum prolactin increased by 32-fold in female rats.

Mutagenesis: The mutagenic potential was tested in a hamster. The bacterial mutation is done in the ovary of the hamster. Quetiapine increased the mutation of Salmonella Typhimurium.

Impairment of Fertility: Administration of 150 mg/kg in the rats decreased fertility. The effect continued for two weeks without treatment. It is 0.6 times the dosage administered in humans on an mg basis.

Pregnancy: Administration of 200 mg/kg in rabbits delayed the skeletal ossification of the fetus. It is 2.4 times the maximum dosage administered in humans. There were changes like reduced fetal body weight and soft tissue anomaly. Maternal toxicity decreased the weight of mother rabbits and resulted in a fatal condition. There is no adequate information about the administration of Quetiapine in pregnant women and its potential effects.

Labor and Delivery: The effect of Quetiapine on labor and delivery cannot be determined.

Nursing Mothers: Quetiapine was excreted in the breast milk during lactation.

Pediatric Use: The safety and efficacy of Quetiapine in pediatric patients were not established.

Geriatric Use: 7% of geriatric patients older than 65 years of age were studied. They did not show any signs of tolerance when compared with young adults. There was poor orthostasis and slow titration. Plasma clearance of Quetiapine decreased to 50% when compared to the young patients.

What Are the Adverse Effects of Quetiapine Fumarate?

Adverse Effects Observed in Short-Term Controlled Trials

Acute Bipolar Mania: 5.7% of patients were asked to discontinue Quetiapine due to adverse effects like acute bipolar mania.

Schizophrenia: 4% of patients were asked to discontinue Quetiapine due to somnolence and hypotension.

Adverse Effects Observed in Short-Term Placebo-Controlled Trials:

Dose-Related Adverse Effects: Studies were conducted after administering Quetiapine in the dosage of 75 mg, 150 mg, 300 mg, 600 mg, and 750 mg for a day. It was found that patients were affected with dyspepsia, abdominal pain, and weight gain.

Extrapyramidal Symptoms: Administering Quetiapine in the five dosage formula of 75 mg, 150 mg, 300 mg, 600 mg, and 750 mg for a day resulted in extrapyramidal symptoms. It caused parkinsonism, akinesia, hypertonia, and neck rigidity.

Vital Sign Changes: Quetiapine was associated with orthostatic hypotension.

Weight Gain: More than 7% of body weight was gained in patients who were studied for three to six weeks of placebo-controlled clinical trials.

Laboratory Changes: Quetiapine was proved to increase the level of total cholesterol and triglyceride levels. The short-term hematological assessment did not prove any difference between placebo and controlled trials.

ECG (Echocardiography) Changes: During the assessment of ECG in placebo and controlled trials, Quetiapine showed an increase in heart rate. It is increased by seven beats per minute. There was a slight variation in tachycardia when Quetiapine was administered.

Nervous System: Patients were observed with involuntary movements, hallucinations, urinary retention, abnormal gait, ataxia, delirium, euphoria, and neuralgia.

Body: Frequent symptoms of neck pain, chills, flu, edema, and rare symptoms of suicide attempts and photosensitivity reactions.

Digestive System: The patients had gingivitis, flatulence, gastritis, stomatitis, mouth ulceration, tongue edema, glossitis, and melena.

Cardiovascular System: The patients had migraine, bradycardia, thrombophlebitis, and T wave abnormality. Rare symptoms include congestive heart failure and increased QRS duration.

Respiratory System: The patient had pharyngitis, cough, asthma, and dyspnea.

Metabolic and Nutritional System: Patients were noticed with increased alkaline phosphatase levels, dehydration, increased creatinine, gout, and hypokalemia.

Skin and Appendages System: Patients had symptoms like rashes, ulcers, eczema, psoriasis, and skin discoloration.

Urogenital System: There were symptoms like vaginitis, cystitis, vaginal hemorrhage, abnormal lactation, polyuria, and acute kidney failure.

Musculoskeletal System: Patients had fractures, twitching, leg cramps, and bone pain.

Special Senses: There were infrequent symptoms like abnormal vision, dry eyes, eye pain, and taste perversion. Symptoms like glaucoma and deafness are rarely seen.

Lymphatic System: There were frequent symptoms like leukopenia and anemia and infrequent symptoms like cyanosis, hemolysis, and eosinophilia.

Endocrine System: Symptoms like hypothyroidism and diabetes mellitus were observed.

What Is the Dosage and Administration for Quetiapine Fumarate?

Acute Bipolar Mania: Quetiapine should be initiated at 100 mg/day twice daily and increased to 400 mg/day. On the sixth day, the dosage can be increased up to 800 mg/day.

Schizophrenia: Quetiapine should be administered in an initial dose of 25 mg twice daily, increased to 50 mg on the third day, to a target dose of 400 mg on the fourth day. During dose adjustments, an increased or decreased dosage of 25 mg to 50 mg is recommended.

Dosing in Specific Populations: Patients with hepatic impairment are administered 25 mg/day. It can be increased in increments of 25 mg/day to 50 mg/day to the maximum dosage.

Maintenance Therapy: There is no evidence to determine the effectiveness of maintenance treatment. It is recommended to use the lowest dose during the maintenance phase.

Reinitiation of Dosage in Patients After Withdrawal: Restarting dose should be less than a week after discontinuation. When the dose is readministered, the initial titration schedule should be maintained.

How is Quetiapine Supplied?

Quetiapine 25 mg tablets appear peach, rounded, and biconvex. They are coated with thin films. They are identified by their name on one side and plain on the other side. They are available in the market in a bottle containing 100 tablets. They are sold as unit dose packages in hospitals.

Quetiapine 100 mg tablets appear yellow, rounded, and biconvex. They are coated with biofilms, as indicated by their name.

Quetiapine 200 mg tablets appear white, rounded, and biconvex and are available in bottles containing 100 tablets.

Quetiapine 300 mg tablets appear white, capsule-shaped, and biconvex. They are supplied in bottles containing 60 tablets.

Animal Toxicology:

Quetiapine causes an increase in pigmentation of the thyroid gland. It was detected in the rat studies conducted for four weeks. The doses administered in rats were 10 mg/kg to 250 mg/kg, while mice were 75 mg/kg to 750 mg/kg. These doses were three to four times lower than the maximum recommended dosage in humans. The thyroid pigmentation was irreversible in rats. It was found mostly on the thyroid follicular cells. The effects and functions of Quetiapine on the thyroid gland in humans are not known.

In dogs, 100 mg/kg was administered for about six months to twelve months. It is four times the recommended dosage in humans. It resulted in the inhibition of cholesterol biosynthesis and cataracts. During the examination of plasma cholesterol levels in dogs, it was found that there was no association between cholesterol levels and cataracts in each dog. The presence of delta-8-cholestanol is analyzed. When the dogs were treated, it was found that cholesterol was reduced by 25 %. Cataract was not found in other animals like monkeys when they were administered with 225 mg/kg. It was five times more than the recommended dosage for humans.

Patient Counseling Information

Orthostatic Hypotension: Patients should be warned about the initial dose titration.

Pregnancy and Nursing: The patient should inform the medical professional about pregnancy or plan to get pregnant before the antipsychotic therapy. Patients who are taking Quetiapine should avoid feeding their children.

Concomitant Medication: The patient should notify the physician about the intake of over-the-counter medications.

Alcohol: Patients taking Quetiapine should avoid alcohol consumption as it causes potential effects on the cognitive and motor effects.

Heat Exposure or Dehydration: Patients should take extra care to avoid dehydration due to overheating.

Laboratory Tests: There is no specific test.

What Are the Instructions to Follow Before Taking Quetiapine?

Inform the physician about the following;

• Underlying medical conditions.

• Mineral or vitamin supplements are taken daily.

• History of cataracts, diabetes, and hypertension.

• History of psychotic disorders.

• Recent history of infection with antipsychotic drugs.

• Recent history of vaccination.

• Avoid stopping Quetiapine Fumarate drug or reducing the dosage without the knowledge of your medical professional.

• Withdrawal of the drug must be done only under the observation of a medical professional.

How to Take Quetiapine Fumarate Tablets?

• Take the dosage as prescribed by your physician.

• Do not co-administer with the drugs that interact with Quetiapine Fumarate.

• Adults should swallow Quetiapine Fumarate tablets using water after food. Avoid breaking it into smaller pieces.

• Avoid the missed dose and take the next dose at the recommended time.

• Follow a regular time interval between two doses.

How to Store Quetiapine Fumarate Tablets?

Quetiapine tablets should be stored at a temperature of 25 degrees Celsius. The excursions are permitted up to 15 degrees Celsius to 30 degrees Celsius. Keep the Quetiapine tablets out of reach from children.

General Information About the Safety and Effective Use of Quetiapine Fumarate:

• Avoid self-medicating with Quetiapine Fumarate for psychotic disorders like schizophrenia and bipolar disorders.

• Close the lid of the bottle after every use.

• Read the instructions given on the back of Quetiapine Fumarate tablets containing bottles.