Saphris^® (Tablets) Instructions for Use

ATC Code

N05AH05 (Asenapine)

Active Substance

Asenapine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

Pharmacological Action

Antipsychotic agent (neuroleptic). The mechanism of action of asenapine, like other drugs effective in the treatment of schizophrenia and bipolar disorder, is not fully understood.

Given the nature of asenapine’s receptor interactions, its efficacy is considered to be due to a combined antagonistic effect on dopamine D₂ and serotonin 5-HT_2A receptors.

Interaction with other receptors, such as serotonin 5-HT_1A, 5-HT_1B, 5-HT_2C, 5-HT₆, 5-HT₇, dopamine D₃, and α₂-adrenergic receptors, may also influence the clinical effects of asenapine.

Pharmacokinetics

After sublingual administration, asenapine is rapidly absorbed, with a plasma C_max reached within 0.5-1.5 hours.

The absolute bioavailability of asenapine at a 5 mg dose when administered sublingually is 35%.

The absolute bioavailability after oral administration is low (<2%).

Ingestion of water 2 or 5 minutes after asenapine administration led to a decrease in asenapine blood concentration (by 19% and 10%, respectively). Therefore, patients should not drink or eat for 10 minutes after taking asenapine.

Increasing the dose from 5 mg to 10 mg twice daily leads to a non-linear increase (1.7-fold) in AUC and C_max.

The disproportionate increase in C_max and AUC with dose escalation may be due to limited absorption through the oral mucosa after sublingual administration.

When asenapine is administered twice daily, steady-state concentration (C_ss) is achieved within 3 days.

Overall, the pharmacokinetics of asenapine at steady state are similar to those after a single dose.

Asenapine is rapidly distributed. The volume of distribution (V_d) is large (approximately 1700 L), indicating active distribution into the extravascular space.

Asenapine is highly (95%) bound to plasma proteins – albumin and α₁-acid glycoprotein.

Asenapine undergoes extensive metabolism. The primary metabolic pathways for asenapine are direct glucuronidation (via the UGT1A4 isoenzyme) and oxidation and demethylation mediated by cytochrome P450 isoenzymes (primarily the CYP1A2 isoenzyme, as well as the 2D6 and 3A4 isoenzymes).

In an in vivo study in humans receiving labeled asenapine, asenapine N⁺-glucuronide was predominantly detected in plasma, along with other metabolites at lower concentrations, including N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine.

Pharmacological activity is primarily due to the unchanged asenapine.

Asenapine is a weak inhibitor of the CYP2D6 isoenzyme. It does not induce CYP1A2 or CYP3A4 isoenzymes in cultured human hepatocytes.

The clearance of asenapine is high and amounts to 52 L/h after intravenous administration.

Most of the dose of radioactively labeled asenapine is excreted by the kidneys (about 50%) and via the intestines (about 40%). Only a small portion of the dose is excreted via the intestines (5-16%) as unchanged asenapine.

After an initial faster distribution phase, the elimination half-life (T_1/2) of asenapine is approximately 24 hours.

The pharmacokinetics of asenapine are similar in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment and patients with normal liver function.

In patients with severe hepatic impairment (Child-Pugh class C), a 7-fold increase in the AUC of asenapine was observed.

The pharmacokinetics of asenapine after a single 5 mg dose were similar in patients with varying degrees of renal impairment and patients with normal renal function.

In elderly patients, the AUC of asenapine was approximately 30% higher than in younger adults.

Indications

Schizophrenia: for acute and maintenance treatment.

Bipolar affective disorder: as monotherapy for the acute treatment of manic or mixed episodes associated with bipolar affective disorder; as adjunctive therapy with lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar affective disorder.

ICD codes

Dosage Regimen

Administer Saphris^® sublingually. Place the tablet under the tongue and allow it to dissolve completely. Do not crush, chew, or swallow the tablet whole.

Do not eat or drink for 10 minutes after administration. Ingestion of food or liquid immediately after dosing reduces bioavailability and compromises efficacy.

For schizophrenia in adults, the recommended starting and maintenance dosage is 5 mg twice daily. The maximum recommended dosage is 10 mg twice daily.

For bipolar I disorder in adults, as monotherapy for acute manic or mixed episodes, the recommended starting dosage is 10 mg twice daily. The dosage may be reduced to 5 mg twice daily if tolerability concerns arise.

For bipolar I disorder as adjunctive therapy with lithium or valproate, the recommended dosage is 5 mg twice daily. The dosage may be increased to 10 mg twice daily based on clinical response.

When used in a combination regimen, administer Saphris^® last. This ensures optimal sublingual absorption without interference from other orally administered medications.

Dose adjustment is not routinely required based on age, gender, race, or renal impairment. Avoid use in patients with severe hepatic impairment (Child-Pugh C) due to a significant increase in drug exposure.

Regularly reassess the need for continued treatment and the appropriate dosage. The duration of therapy is indefinite and depends on the indication, therapeutic response, and the patient’s clinical status.

Adverse Reactions

Nervous system disorders: very common – drowsiness; common – akathisia, parkinsonism, dizziness, dystonia, dysgeusia, dyskinesia, sedative effect; uncommon – dysarthria, syncope, extrapyramidal disorders, seizures; rare – NMS.

Psychiatric disorders: very common – anxiety.

Gastrointestinal disorders: common – oral hypoesthesia, increased ALT activity; uncommon – oral paresthesia, glossodynia, tongue edema, dysphagia.

Cardiovascular disorders: uncommon – sinus bradycardia, bundle branch block, QT interval prolongation on ECG, orthostatic hypotension, arterial hypotension.

Hematopoietic system disorders: rare – neutropenia.

Metabolism and nutrition disorders: common – weight gain, increased appetite; uncommon – hyperglycemia.

Respiratory system disorders: rare – pulmonary embolism.

Musculoskeletal and connective tissue disorders: common – muscle rigidity; rare – rhabdomyolysis.

Reproductive system and breast disorders: uncommon – sexual dysfunction, amenorrhea; rare – gynecomastia, galactorrhea.

General disorders and administration site conditions: common – fatigue; frequency unknown – allergic reactions, neonatal withdrawal syndrome.

Contraindications

Age under 18 years; lactation (breastfeeding); hypersensitivity to asenapine.

Use in Pregnancy and Lactation

Asenapine is not recommended during pregnancy, except in cases where the potential benefit to the patient significantly outweighs the possible risk to the fetus.

It is not known whether asenapine or its metabolites are excreted in human breast milk.

Experimental studies have shown that asenapine is excreted in the milk of lactating rats. The use of asenapine during lactation is contraindicated.

Special Precautions

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Asenapine is not recommended for the treatment of patients with dementia-related psychosis.

Cases of neuroleptic malignant syndrome (NMS), characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase (CPK) levels, have been reported during treatment with antipsychotic drugs, including asenapine.

Additional manifestations may include myoglobinuria (rhabdomyolysis) and acute renal failure. If symptoms of NMS appear, asenapine should be discontinued.

Use with caution in patients with a history of seizures or conditions associated with seizures.

Suicidal attempts may be observed in psychotic illnesses and bipolar disorder, so treatment of patients at high risk of suicide should be under strict supervision.

A 7-fold increase in asenapine concentration was observed in patients with severe hepatic impairment (Child-Pugh class C). Therefore, the use of Asenapine is not recommended in this category of patients.

Asenapine may cause orthostatic hypotension and syncope, especially at the start of treatment, which may reflect its α₁-adrenergic blocking properties.

Elderly patients are particularly at risk of developing orthostatic hypotension. Asenapine should be used with caution in elderly patients and in patients with cardiovascular diseases (e.g., heart failure, myocardial infarction or ischemia, conduction disorders), cerebrovascular disease, or conditions that predispose to hypotension (e.g., dehydration and hypovolemia).

The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If symptoms of tardive dyskinesia appear, discontinuation of treatment should be considered.

An increase in prolactin concentration was observed in some patients treated with Asenapine. Isolated cases of adverse events associated with elevated blood prolactin levels have been observed.

Treatment with asenapine is probably not associated with a clinically significant prolongation of the QT interval. However, caution should be exercised when using asenapine in patients with cardiovascular disease or a family history of long QT syndrome, and during concomitant therapy with other drugs that prolong the QT interval.

Hyperglycemia and exacerbations of pre-existing diabetes have been observed during treatment with asenapine.

Establishing a link between the use of atypical antipsychotics and impaired glucose metabolism is complicated by the increased risk of diabetes in patients with schizophrenia or bipolar disorder, and the increasing incidence of diabetes in the general population.

Regular clinical monitoring of patients with diabetes and patients with risk factors for this disease is recommended.

Treatment with antipsychotic drugs may be accompanied by impaired thermoregulation. Clinically significant changes in thermoregulation did not develop with the use of asenapine.

During treatment with asenapine, patients should receive appropriate care if conditions and situations arise that contribute to an increase in body temperature, for example, physical exercise, exposure to high temperatures, dehydration, or concomitant use of drugs with anticholinergic activity.

During treatment, patients should avoid consuming alcohol.

Effect on the ability to drive vehicles and operate machinery

Asenapine may cause drowsiness and a sedative effect. Therefore, during treatment, patients should not drive vehicles or operate machinery until the nature of the adverse effects of asenapine is established.

Drug Interactions

Asenapine has an effect on the CNS, so caution should be exercised when using it in combination with other centrally acting drugs.

Asenapine is metabolized mainly by direct glucuronidation via the UGT1A4 isoenzyme and oxidative metabolism via cytochrome P450 isoenzymes (primarily the CYP1A2 isoenzyme).

Concomitant use with fluvoxamine (a CYP1A2 isoenzyme inhibitor) at a full therapeutic dose may cause a more pronounced increase in asenapine plasma concentration.

Since Asenapine has α₁-adrenergic blocking properties and can cause orthostatic hypotension, combination may enhance the effects of some antihypertensive drugs.

Asenapine has a weak inhibitory effect on the CYP2D6 isoenzyme. Use with caution in combination with drugs that are substrates or inhibitors of the CYP2D6 isoenzyme.

Concomitant single-dose administration of 20 mg paroxetine (a substrate and inhibitor of the CYP2D6 isoenzyme) during administration of asenapine 5 mg twice daily in healthy male volunteers led to an almost 2-fold increase in the AUC of paroxetine. However, asenapine may enhance the inhibitory effects of paroxetine on its own metabolism.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.