For the use of a Registered Medical Practitioner only

1.GENERIC NAMEAND BRAND NAME
Escitalopram Oxalate & Clonazepam Tablets I.P.
Szetalo Plus^®
Szetalo Plus^® 5

2. QUALITATIVE AND QUANTITATIVE COMPOSITION:
Szetalo Plus^®
Each film coated tablet contains:
Escitalopram Oxalate IP
Equivalent to Escitalopram 10 mg
Clonazepam I.P. 0.5 mg
Colour: Red oxide of Iron & Titanium Dioxide I.P.

Szetalo Plus^® 5
Each film coated tablet contains:
Escitalopram Oxalate IP
Equivalent to Escitalopram 5 mg
Clonazepam I.P. 0.5 mg
Colour: Titanium Dioxide IP

3. DOSAGE FORM AND STRENGTH
Refer section 1&2

4.CLINICAL PARTICULARS

4.1 THERAPEUTIC INDICATIONS
For the treatment of co-morbid depression with anxiety disorder.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION
One Tablet once in a day orally or as directed by physician. Fixed dose combination may be replaced by Escitalopram after initial treatment of 2-3 weeks.

4.3 CONTRAINDICATIONS

• Hypersensitivity to benzodiazepines or to other ingredients of the medicinal product.
• Escitalopram is not recommended in combination with monoamine oxidase inhibitors (MAOI) or the reversible MAOI (RIMA), moclobemide or within 14 days of discontinuing treatment with a MAOI and at least one day after discontinuing treatment with the reversible MAOI (RIMA), moclobemide.
• Concomitant use in patients taking pimozide is contraindicated.
• Severe respiratory insufficiency
• Severe hepatic insufficiency
• Acute pulmonary insufficiency
• Sleep apnoea syndrome
• Myasthenia gravis
• Narrow angle glaucoma

4.4 SPEACIAL WARNINGS AND PRECAUTIONS FOR USE
It contains two drugs escitalopram and clonazepam. Hence warnings and precautions applicable to both the drugs must be considered

• Keep out of reach of children.
• Patients should be advised to avoid alcohol
• Patients should be cautioned when they undertake any jobs that require mental alertness such as driving, operating machinery.
• Avoid abrupt discontinuation of this drug .Gradual reduction over a period of 1 to 2 weeks is advised due to clonazepam in the formulation
• Breast feeding is not recommended when women are taking this drug due to clonazepam

Escitalopram

• Clinical Worsening and Suicide Risk- Monitor for clinical worsening, suicidality & unusual change in behavior, especially during the initial few months of therapy or at time of dose change.
• Serotonin Syndrome – During treatment initiation patients should be made aware of a potential increased risk for serotonin syndrome.
• Seizures- Use cautiously in patients with history of seizures.
• Activation of Mania/Hypomania – Use cautiously in patients with history of mania.
• Abnormal Bleeding – Use cautiously in concomitant use with NSAIDS, aspirin, warfarin or other drugs that effect coagulation.
• Hyponatremia- can occur in association with SIADH.
• Pregnancy- Caution should be exercised when administered during pregnancy.
• Pediatric Use – No data available. Escitalopram must not be used in children and adolescents under 18 years of age
• Concomitant use with the following drugs is contraindicated: St Johns’ wort, MAOI or within 14 days of discontinuing treatment with MAOI.

Clonazepam

• General: A paradoxical increase in seizure activity or the appearance of new seizure types has occurred in a very few patients during treatment with clonazepam.
• The concomitant use of alcohol and/or CNS depressants should be avoided.
• Medical history of alcohol or drug abuse – clonazepam should be used with extreme caution in patients with a history of alcohol or drug abuse.
• Lactose intolerance- Lactose is a non-medicinal ingredient in clonazepam. Therefore, patients with rare hereditary problems of galactose intolerance &Lapp lactase deficiency or glucose-galactosemal absorption should not take this medicine.
• Hepatic- No safety & efficacy data available
• Respiratory – Respiratory depression may occur following administration of drug.
• Special Populations Pregnant Women-Studies indicate anco relation between the use of anticonvulsant drugs and an elevated incidence of birth defects in children born to epileptic women taking such medication during pregnancy.
• Nursing Women- The mothers receiving clonazepam should not breast-feed their infants.
• Pediatrics (< 5 years of age)- The risk-benefit consideration of the long-term use of clonazepam is important in pediatric patients.
• Geriatrics: There is no clinical trial experience with clonazepam in seizure disorder patients 65 years of age and older
• Prolonged use of clonazepam may result in dependence and withdrawal symptoms on cessation of treatment

4.5 DRUG INTERACTIONS
1. Coadministration of Escitalopram with the following drugs
Interaction with Monoamine Oxidase Inhibitors (MAOIs):
Escitalopram should not be used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should be allowed after stopping escitalopram, before starting a MAOI since there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma when selective serotonin reuptake inhibitors (SSRIs) were coadministered with MAOIs. Such reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on a MAOI.
CNS Drugs:  Caution advised when concomitant use is necessary.
Alcohol: Concomitant use is not recommended.
NSAIDs, Aspirin, Warfarin: There is reported association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.  It is also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, concurrent use of such drugs should be avoided.
Lithium:  Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised and plasma lithium levels should be monitored with appropriate adjustment to the lithium dose
Sumatriptan: Caution advised and appropriate observation of the patient is warranted.
Carbamazepine:  carbamazepine might increase the clearance of escitalopram.
Pimozide: Rarely increase in QTc values the mechanism of this pharmacodynamic interaction is not known.
Drugs Metabolized by Cytochrome P4502D6:  Caution is advised in the coadministration of escitalopram and drugs metabolized by CYP2D6.Escitalopram Drug Interaction with

2.Coadministration clonazepam with the following drugs
Alcohol:  To be totally avoided. Since alcohol can provoke epileptic seizures, irrespective of therapy, patients must under no circumstances drink alcohol while under treatment. In combination with clonazepam, alcohol may modify the effects of the drug, compromise the success of therapy or give rise to unpredictable side-effects.
Anti-epileptic drugs: When clonazepam is used in conjunction with other antiepileptic drugs, side-effects such as sedation and apathy, and toxicity may be more evident, particularly with hydantoins or phenobarbital and combinations including them. This requires extra care in adjusting dosage in the initial stages of treatment.
The combination of clonazepam and sodium valproate has, rarely, been associated with the development of absence status epilepticus. Although some patients tolerate and benefit from this combination of drugs, this potential hazard should be borne in mind when its use is considered.
Inhibitors of hepatic enzymes:  Known inhibitors of hepatic enzymes, e.g. cimetidine, have been shown to reduce the clearance of benzodiazepines and may potentiate their action and known inducers of hepatic enzymes, e.g. rifampicin, may increase the clearance of benzodiazepines.
Co-administration of escitalopram with cimetidine 400 mg twice daily (moderately potent general enzyme inhibitor) resulted in a moderate (approximately 70%) increase in the plasma concentrations of escitalopram. Caution is advised when administering escitalopram in combination with cimetidine. Dose adjustment may be warranted.
Thus, caution should be exercised when used concomitantly with CYP2C19 inhibitors (e.g. omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine, fluconazole) or cimetidine. A reduction in the dose of escitalopram may be necessary based on monitoring of side-effects during concomitant treatment.
Phenytoin or primidone:  In concurrent treatment with phenytoin or primidone, a change, usually a rise in the serum concentration of these two substances has occasionally been observed.
Centrally Acting Drugs:  Concurrent use of clonazepam and other centrally acting medications, e.g. other anticonvulsant (antiepileptic) agents, anaesthetics, hypnotics, psychoactive drugs and some analgesics as well as muscle-relaxants may result in mutual potentiation of drug effects. This is especially true in the presence of alcohol. In combination therapy with centrally-acting medications, the dosage of each drug must be adjusted to achieve the optimum effect

4.6 USE IN SPECIAL POPULATIONS (SUCH AS PREGNANT WOMEN, LACTATING WOMEN, PAEDIATRIC PATIENTS, GERIATRIC PATIENTS ETC.)
Escitalopram
Pregnancy

For escitalopram only limited clinical data are available regarding exposed pregnancies. Animal studies have shown reproductive toxicity . Escitalopram should not be used during pregnancy unless clearly necessary and only after careful consideration of the risk/benefit.

Neonates should be observed if maternal use of Escitalopram continues into the later stages of pregnancy, particularly in the third trimester. Abrupt discontinuation should be avoided during pregnancy.

The following symptoms may occur in the neonate after maternal SSRI/SNRI use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either serotonergic effects or discontinuation symptoms. In a majority of instances, the complications begin immediately or soon (<24 hours) after delivery.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

Breastfeeding

It is expected that escitalopram will be excreted into human milk.

Consequently, breast-feeding is not recommended during treatment.

Clonazepam
Pregnancy

During pregnancy, Clonazepam may be administered only if there is a compelling indication. Clonazepam has harmful pharmacological effects on pregnancy and the foetus/newborn child. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heart beat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the post-natal period. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy. Therefore, clonazepam should not be used in pregnancy unless clearly necessary.

Breast-feeding
Although clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this drug should not breastfeed. If there is a compelling indication for clonazepam, breastfeeding should be discontinued.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Escitalopram
Although escitalopram has been shown not to affect intellectual function or psychomotor performance, any psychoactive medicinal product may impair judgement or skills. Patients should be cautioned about the potential risk of an influence on their ability to drive a car and operate machinery

Clonazepam
clonazepam can slow reactions to such an extent that the ability to drive a vehicle or operate machinery is impaired.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely.

4.8 UNDESIRABLE EFFECTS
Seizure Disorders
The most frequently occurring side effects are related to CNS depression. Drowsiness, ataxia, behaviour.
Neurologic: Abnormal eye movements, aphonia, choreiform movements, coma, diplopia, dysarthria, dysdiadochokinesis, ”glassy-eyed” appearance, headache, hemiparesis, hypotonia, nystagmus, respiratory depression, slurred speech, tremor, vertigo.
Psychiatric: Reduced intellectual ability, confusion, depression, amnesia, hallucinations, hysteria, increased libido, insomnia, psychosis (the behaviour effects are more likely to occur in patients with a history of psychiatric disturbances). Paradoxical reactions have been observed such as: excitability, irritability, aggressive behaviour, agitation, nervousness, panic disorder hostility, anxiety, sleep disturbances, nightmares and vivid dreams.
Respiratory: Rhinorrhea, chest congestion, dyspnea, hypersecretion in upper respiratory passages
Cardiovascular: Palpitations
Dermatologic: Hair loss, hirsutism, skin rash, ankle and facial edema
Gastrointestinal: Anorexia, coated tongue, dry mouth, encopresis, gastritis, increased appetite, nausea, sore gums, constipation, diarrhea.
Genitourinary: Dysuria, enuresis, nocturia, urinary retention, Persistent Sexual dysfunction after drug withdrawal
Musculoskeletal: Muscle weakness, pains
Miscellaneous: Dehydration, general deterioration, fever, lymphadenopathy, weight changes such as weight loss or weight gain
Hematopoietic: Anemia, leukopenia, thrombocytopenia, eosinophilia
Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase

4.9 OVERDOSAGE
Escitalopram
Toxicity
Clinical data on escitalopram overdose are limited and many cases involve concomitant overdoses of other drugs. In the majority of cases mild or no symptoms have been reported. Fatal cases of escitalopram overdose have rarely been reported with escitalopram alone; the majority of cases have involved overdose with concomitant medications. Doses between 400 and 800mg of escitalopram alone have been taken without any severe symptoms.

Symptoms
Symptoms seen in reported overdose of escitalopram include symptoms mainly related to the central nervous system (ranging from dizziness, tremor, and agitation to rare cases of serotonin syndrome, convulsion, and coma), the gastrointestinal system (nausea/vomiting), and the cardiovascular system (hypotension, tachycardia, QT interval prolongation, and arrhythmia) and electrolyte/fluid balance conditions (hypokalemia, hyponatremia).

Management
There is no specific antidote. Establish and maintain an airway, ensure adequate oxygenation and respiratory function. Gastric lavage and the use of activated charcoal should be considered. Gastric lavage should be carried out as soon as possible after oral ingestion. Cardiac and vital signs monitoring are recommended along with general symptomatic supportive measures.
ECG monitoring is advised in case of overdose in patients with congestive heart failure/bradyarrhythmia’s, in patients using concomitant medications that prolong the QT interval, or in patients with altered metabolism, e.g. liver impairment.

Clonazepam
As with other benzodiazepine drugs, overdosage should not present undue problems of management or threat to life. Patients have recovered from overdoses in excess of 60mg without special treatment. Severe somnolence with muscle hypotonia will be present.

5.0 PHARMACOLOGIC PROPERTIES
5.1 MECHANISM OF ACTION
Kindly refer to section 5.2

5.2 PHARMACODYNAMIC PROPERTIES
Escitalopram is a potent inhibitor of serotonin (5- HT)-uptake (in vitro IC50 2 nM). The antidepressant action of escitalopram is presumably linked to the potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibitory effect on the reuptake of 5-HT from the synaptic cleft.
Escitalopram has high affinity for the primary binding site and an allosteric modulating effect on the serotonin transporter. The Allosteric modulation of the serotonin transporter enhances binding of escitalopram to the primary binding site, resulting in more complete serotonin reuptake inhibition.
Clonazepam is an anticonvulsant which exhibits several pharmacological properties characteristic of the benzodiazepine class of medicines.
Benzodiazepines increase the polysynaptic inhibitory processes at all levels of the central nervous system. Clonazepam is more effective in blocking spread of electrical activity in the lesion itself.
The exact site and mode of action of the anticonvulsant action of clonazepam is unknown.

5.3 PHARMACOKINETIC PROPERTIES

6.NONCLINICAL PROPERTIES
6.1 ANIMAL TOXICOLOGY OR PHARMACOLOGY
Escitalopram
Animal data have shown that citalopram induces a reduction of fertility index and pregnancy index, reduction in number in implantation and abnormal sperm at exposure well in excess of human exposure. No animal data related to this aspect are available for escitalopram.
Clonazepam
Carcinogenicity
No 2-year carcinogenicity studies have been conducted with clonazepam. However, in an 18-month chronic study in rats no treatment-related histopathological changes were seen up to the highest tested dose of 300 mg/kg/day.
Mutagenicity
Genotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for clonazepam.

Impairment of Fertility
Studies assessing fertility and general reproductive performance in rats showed a reduced pregnancy rate and impaired pup survival at doses of 10 and 100 mg/kg/day.
Teratogenicity
No adverse maternal or embryo-fetal effects were observed in either mice or rats following administration of oral clonazepam during organogenesis, at doses of up to 20 or 40 mg/kg/day, respectively.
In several rabbit studies following doses of clonazepam of up to 20 mg/kg/day, a low, non-dose-related incidence of a similar pattern of malformations (cleft palate, open eyelids, fused stern brae and limb defects) was observed

7.0 DESCRIPTION
Szetalo Plus®
SZETALO PLUS is supplied for oral administration, as a film coated tablet of Escitalopram Oxalate & Clonazepam. Each film coated tablet of SZETALO PLUS contains Escitalopram Oxalate equivalent to Escitalopram 10 mg & Clonazepam 0.5 mg.

Szetalo Plus^® 5
SZETALO PLUS 5 is supplied for oral administration, as a film coated tablet of Escitalopram Oxalate & Clonazepam. Each film coated tablet of SZETALO PLUS 5 contains Escitalopram Oxalate equivalent to Escitalopram 5 mg & Clonazepam 0.5 mg.

8.0 PHARMACEUTICAL PARTICULARS
8.1 INCOMPATIBILITIES
Not Applicable

8.2 SHELF-LIFE
Refer pack

8.3 PACKAGING INFORMATION
Refer pack

8.4 STORAGE CONDITION AND HANDING INSTRUCTIONS
Refer pack

9. PATIENT COUNSELLING INFORMATION
It contains two drugs escitalopram and Clonazepam. Hence warnings and precautions applicable to both the drugs must be considered.

• Keep out of reach of children.
• Patients should be advised to avoid alcohol
• Patients should be cautioned when they undertake any jobs that require mental alertness such as driving, operating machinery.
• Avoid abrupt discontinuation of this drug. Gradual reduction over a period of 1 to 2 weeks is advised due to clonazepam in the formulation
• Breast feeding is not recommended when women are taking this drug due to clonazepam (refer section 4.4 for more details)

General Information about Medication Guide:
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with this tablet and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for this tablet (Escitalopram/Clonazepam).
The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.
Pregnancy and Breast Feeding:
Patients should be advised to notify their physician if they
• become pregnant or intend to become pregnant during therapy.
• are breastfeeding an infant.
Alcohol:
Patients should be told that, although it has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of this tablet and alcohol is not advised.
Interference with Psychomotor Performance:
Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Escitalopram/Clonazepam therapy does not affect their ability to engage in such activities.
Abnormal Bleeding:
Patients should be cautioned about the concomitant use of escitalopram and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Angle Closure Glaucoma:
Patients should be advised that taking this tablet can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma.
Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

Information for patients:

• Do not stop the treatment without first talking to a healthcare provider.
• Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements.
• Taking this tablet with certain other medicines can cause side effects or affect how well the treatment or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.
• It can cause abuse and dependence.
• Do not stop taking this tablet all of a sudden. Stopping it suddenly can cause seizures that do not stop, hearing or seeing things that are not there (hallucinations), shaking, and stomach and muscle cramps.
• Talk to your healthcare provider about slowly stopping the treatment to avoid withdrawal symptoms.
• Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.
• Clonazepam is a benzodiazepine medicine. Benzodiazepines can cause severe drowsiness, breathing problems (respiratory depression), coma, and death when taken with opioid medicines.
• Clonazepam can make you sleepy or dizzy and can slow your thinking and motor skills. This may get better over time.
• Do not drive, operate heavy machinery, or do other dangerous activities until you know how Clonazepam affects you.
• Clonazepam may cause problems with your coordination, especially when you are walking or picking things up.
• Do not use this tablet for a condition for which it was not prescribed. Do not give it to other people, even if they have the same condition. It may harm them.

10. DETAILS OF MANUFACTURER
Refer Pack for manufacturer details.

MARKETED BY
Abbott Healthcare Pvt. Ltd.
Angel Space, Bldg. D-4, Gala No. 1 to 6 & ,
11 to 16 Ground Floor, 101 to 106 &
111 to 116 First Floor, 201 to 206 & 211 to 216
2^nd Floor, Pimplas, Dist. Thane, Bhiwandi – 421 302, India.

11. DETAILS OF PERMISSION OR LICENCE NUMBER

Refer Pack for Permission/License details

12. DATE OF REVISION
Version 5.0, Dated 16^th Oct 2023

® – Regd. Trade Mark Abbott Healthcare Pvt. Ltd

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