ACTIGRIP DAY&NIGHT 12+4 TABLETS

ACTIGRIP DAY & NIGHT COMPRESSED

active principles

One white tablet (day) contains: active ingredients: paracetamol 500 mg, pseudoephedrine hydrochloride 60 mg; One light blue coated tablet (night) contains: active ingredients: paracetamol 500 mg, diphenhydramine hydrochloride 25 mg. For the complete list of excipients, see section 6.1.

Exceptions

One white tablet (day) contains: microcrystalline cellulose, pregelatinised maize starch, croscarmellose sodium, magnesium stearate, povidone, crospovidone, stearic acid. One light blue coated tablet (night) contains: microcrystalline cellulose, maize starch, sodium starch glycollate, hydroxypropyl cellulose, pregelatinised maize starch, croscarmellose sodium, stearic acid, magnesium stearate, hypromellose, Opadry blue 02H205000 (containing propylene glycol)..

Therapeutic indications

Treatment of cold and flu symptoms.

Contraindications

§ Hypersensitivity to the active substances or to any of the excipients listed in section 6.1; § Children under 12; § Confirmed or presumed pregnancy, breastfeeding; § Cardiovascular diseases, hypertension; § Patients with a history of stroke or predisposing risk factors; § Diabetes; § Glaucoma; § Stenosis of the gastrointestinal tract; § Hyperthyroidism; § Prostatic hypertrophy, stenosis of the urogenital system; § Asthma; § In patients treated with monoamine oxidase inhibitors (MAOIs) and in the two weeks following such treatment; § Patients with a history of seizures, epilepsy. Furthermore, due to the paracetamol content, ACTIGRIP DAY & NIGHT is contraindicated in patients with manifest glucose-6-phosphate dehydrogenase insufficiency.

Posology

Posology. . Adults and children over 12 years of age: one white tablet three times a day (morning, noon and afternoon) plus one blue tablet in the evening before going to bed. After 3 days of continuous use without appreciable results or if high fever or other undesirable effects appear, stop the treatment. Do not exceed the recommended dose. Method of administration. Take the tablets orally, without chewing them.

Storage

Store at a temperature not exceeding 25°C. Store in the original package in order to protect from light and moisture.

Warnings

The use of ACTIGRIP DAY & NIGHT must be avoided in conjunction with analgesics and antipyretics. High doses or prolonged administration of paracetamol, present in the medicine or in other drugs containing paracetamol, can cause high-risk liver disease, alterations in the kidney and blood, even serious ones, and other serious adverse reactions. In adults and children over 12 years of age, the total dose of paracetamol should not exceed 4g per day. Paracetamol should be administered with caution to patients with mild to moderate hepatocellular insufficiency (including Gilbert's syndrome), severe hepatic insufficiency (Child-Pugh > 9), acute hepatitis, concomitant treatment with drugs affecting liver function, of glucose-6-phosphate dehydrogenase, haemolytic anemia. In case of simultaneous treatment with anticoagulant or antiplatelet drugs, the doses of ACTIGRIP DAY & NIGHT must be reduced. Skin safety. Serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported very rarely in patients treated with paracetamol. In the early stages of therapy, patients appear to be at higher risk: the onset of the reaction occurs in most cases in the early stages of treatment. Serious skin reactions such as acute generalized exanthematous pustulosis (AGEP) can occur with products containing pseudoephedrine. This acute pustular eruption may occur within the first 2 days of treatment, with fever and numerous, small, mostly non-follicular pustules resulting from a widespread oedematous erythema and located mainly on skin folds, trunk and upper limbs. Patients should be closely monitored. If signs and symptoms such as pyrexia, erythema or numerous small pustules are observed, the administration of ACTIGRIP DAY & NIGHT should be discontinued and appropriate measures taken if necessary (see section 4.8). Patients should be informed of the signs of serious skin reactions. ACTIGRIP DAY & NIGHT should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Do not use with any other diphenhydramine-containing products, including those for topical use. Cardiovascular and cerebrovascular safety. Patients should be informed that the treatment should be discontinued in case of the following symptoms associated with the pseudoephedrine content: arterial hypertension, tachycardia, palpitations or cardiac arrhythmia, nausea or any neurological sign (insurgence or exacerbation of headache). Ischemic colitis. A few cases of ischemic colitis have been reported with medicinal products containing pseudoephedrine. If sudden abdominal pain, rectal tenesmus, rectal bleeding, or other symptoms of ischemic colitis develop (see section 4.8), the use of pseudoephedrine should be discontinued and a physician consulted. If symptoms persist or worsen, or if new symptoms appear, patients should discontinue use of the medicinal product and consult a doctor. In the rare cases of allergic reactions, the administration of ACTIGRIP DAY & NIGHT must be suspended. Paracetamol should be used with caution in people with renal insufficiency or liver problems. Persons suffering from alcoholism should consult their doctor before taking paracetamol or other pain relievers or antipyretics. Patients with the following respiratory conditions should be advised to consult a physician before using dephenhydramine: emphysema, chronic bronchitis. They should not take pseudoephedrine unless your doctor deems it necessary: patients with reduced kidney function and patients with thyroid disease; do not use in patients suffering from hyperthyroidism (see section 4.3). Due to the paracetamol content, the administration of ACTIGRIP DAY & NIGHT can interfere with the determination of uric acid (by means of the phosphotungstic acid method) and with that of glycemia (by means of the glucose-oxidase-peroxidase method). For who plays sports: the use of the drug without therapeutic need constitutes doping and can in any case determine positivity in anti-doping tests. ACTIGRIP DAY & NIGHT can cause drowsiness. See section 4.8 Undesirable effects.

Interactions

Concomitant use of ACTIGRIP DAY & NIGHT with tricyclic antidepressants, sympathomimetics (e.g. decongestants, anorectics and amphetamine-like), or with MAOIs can interfere with the catabolism of catecholamines and can occasionally cause blood pressure increases. Acute hypertensive crises with concomitant use of MAOIs and sympathomimetic amines have been reported in the medical literature. The effects of anticholinergic drugs (for example atropine and other psychotropic drugs) can be enhanced by the concomitant use of ACTIGRIP DAY & NIGHT. Patients should be advised that additive effects can occur with alcohol, hypnotics, sedatives and tranquilizers and therefore should not be taken together. Use with extreme caution and under strict supervision during chronic treatment with drugs that can cause hepatic monooxygenase induction or in case of exposure to substances that can have this effect (e.g. rifampicin, cimetidine, antiepileptics such as glutethimide, phenobarbital, carbamazepine) . Concomitant use of antihistamines with certain ototoxic antibiotics may mask early signs of ototoxicity, which may only reveal itself when the damage is irreversible. The habitual intake of anticonvulsant drugs or oral contraceptives can, with an enzymatic induction mechanism, accelerate the metabolism of paracetamol, decreasing the plasma concentration, increasing its elimination rate. The rate of absorption of paracetamol can be increased by the concomitant intake of metoclopramide and domperidone and decreased by cholestyramine. Treatment with probenecid can lead to a decrease in paracetamol clearance and an increase in its half-life in the blood. The use of the product is not recommended if the patient is being treated with antipyretics and other analgesics (NSAIDs, COX-2 selective inhibitors, corticosteroids). Due to the pseudoephedrine content, the effect of antihypertensives that interfere with sympathetic activity (e.g. methyldopa, alpha and beta blockers, debrisoquine, guanethidine, betanidine and bretylium) can be partially canceled by ACTIGRIP DAY & NIGHT, which therefore does not must be taken at the same time. Anticoagulants such as warfarin and other coumarins should not be taken simultaneously with ACTIGRIP DAY & NIGHT as their effect can be increased by prolonged use of paracetamol with a greater risk of bleeding.

Effects

Below are the reported adverse reactions reported with a frequency ≥1%, identified in 12 randomized studies controlled with placebo, with formulations containing pseudophedrine as a single active ingredient.

Classification by organs and systems Preferred Term	Pseudofedrine 60 mg single dose(N=229)% (frequency)	Pseudoephedrine 60-120 mg multiple dose (N=496)% (frequency)	Placebo(N=709)% (frequency)
Gastrointestinal pathologies
Dry mouth	\	3.6 (Common)	1.0 (Common)
Nausea	4.4 (Common)	0.2	1.3 (Common)
Pathologies of the nervous system
Dizziness	5.2 (Common)	0.4	2.0 (Common)
Psychiatric disorders
Insomnia	2.2 (Common)	4.6 (Common)	0.3
Nervousness	2.6 (Common)	1.8 (Common)	0.7

The undesirable effects recorded after taking ACTIGRIP DAY & NIGHT are listed below. The frequency of undesirable effects is defined using the following convention: Very common (≥1/10); Common (≥1/100 and Very common side effects: Gastrointestinal pathologies: Abdominal or stomach pain, dyspepsia, diarrhea and vomiting, dry throat. Pathologies of the nervous system: headache, drowsiness, sedation, excitement, increased sweating, sleep disturbances. Eye pathologies: impaired vision. Skin and subcutaneous tissue disorders: skin rashes, urticaria. Respiratory, thoracic and mediastinal disorders: dry nose. Common side effects: Skin and subcutaneous tissue disorders: itching, contact dermatitis, inflammation of the skin or mucous membranes. Heart pathologies: orthostatic/postural hypotension, arrhythmia, tachycardia. Pathologies of the nervous system: tinnitus, ataxia, euphoria and tremors, hypotension, decreased mucous secretions. Eye pathologies: diplopia, impaired vision, glaucoma, angle-closure glaucoma. Gastrointestinal pathologies: Epigastrium disorders. Respiratory, thoracic and mediastinal disorders: dyspnoea. Renal and urinary disorders: urinary retention. Metabolism and nutrition disorders: hyperamylasemia. General disorders and administration site conditions: fatigue, asthenia. Hepatobiliary pathologies: liver function disorders. Uncommon side effects: Skin and subcutaneous tissue disorders: fixed drug eruption (FDE), erythema multiforme, exanthema. Renal and urinary disorders: acute renal failure, interstitial nephritis, hematuria, anuria. Gastrointestinal pathologies: constipation. Respiratory, thoracic and mediastinal disorders: sneezing, dryness of the pharynx and bronchial tree. Skin and subcutaneous tissue disorders: photosensitization. Pathologies of the nervous system: central depression, mental confusion, impaired cognitive function Rare side effects: Endocrine pathologies: hyperthyroidism. Renal and urinary disorders: renal papillary necrosis. Pathologies of the nervous system: hallucinations and nightmares secondary delusions, anxiety, psychiatric disorders, severe headaches, impaired memory or concentration, convulsions Pathologies of the hemolymphopoietic system: blood dyscrasias, agranulocytosis, anemia, hemolytic anemia, thrombocytopenia. Immune system disorders: anaphylactic shock, laryngeal edema. Hepatobiliary pathologies: hepatitis. Gastrointestinal pathologies: pancreatitis. Very rare side effects: Pathologies of the hemolymphopoietic system: leucopenia, neutropenia, pancytopenia. Heart pathologies: angina, ST segment increase, myocardial infarction, hypertension, edema. Skin and subcutaneous tissue disorders: angioedema Hepatobiliary pathologies: hepatotoxicity. Immune system disorders: toxic shock syndrome. Not known side effects: Pathologies of the nervous system: confusional state, irritability, agitation, coordination abnormal, paraesthesia, psychomotor hyperactivity, feeling jittery, cerebrovascular accident* Diagnostic tests: transaminases increased, blood pressure increased. Skin and subcutaneous tissue disorders: itchy rash, severe skin reactions, including acute generalized exanthematous pustulosis (AGEP) (see section 4.4). . Renal and urinary disorders: dysuria. Respiratory, thoracic and mediastinal disorders: chest discomfort. Heart pathologies: palpitations. Immune system disorders: hypersensitivity.Psychiatric disorders: visual hallucination. Gastrointestinal disorders: ischemic colitis* (see section 4.4). *adverse reactions collected during post-marketing experience with pseudoephedrine Reporting of suspected adverse reactions The reporting of suspicious adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit/risk ratio of the medicinal product. Healthcare workers are required to report any suspected adverse reaction via the national reporting system at the address “ http://www.agenziafarmaco.gov.it/content/comesegnalare-una-sospetta-reazione-avversa.”.

Overdose

Keep out of reach of children. In case of overdose, get help from your doctor or contact a poison control center right away. Paracetamol In the event of an overdose, immediate treatment is essential. Despite the absence of early symptoms, gastric lavage is required within 4 hours of taking quantities greater than 7.5 g of paracetamol; the administration of oral methionine or intravenous N-acetylcysteine is recommended within 48 hours. In the first 24 hours following an overdose, the following may occur: pallor, nausea, vomiting, diaphoresis, anorexia, abdominal pain and general malaise. Liver toxicity may not be apparent by clinical and laboratory tests until 48-72 hours after ingestion, and abnormal glucose metabolism and metabolic acidosis may occur. The following are clinical events associated with paracetamol overdose, which are considered to be expected, including fatal events due to fulminant hepatic failure, or its consequences. Table n.1: Adverse drug reactions reported in cases of paracetamol overdose.

SOC	Reporting of suspected adverse reactions
Metabolism and nutrition disorders	Anorexia
Gastrointestinal pathologies	Vomiting, nausea, abdominal discomfort
Hepatobiliary pathologies	Liver necrosis, acute liver failure, jaundice, hepatomegaly, liver tenderness.
General disorders and administration site conditions	Pallor, hyperhidrosis, malaise.
Diagnostic tests	Blood bilirubin increased, liver enzymes increased, international normalized ratio increased, prothrombin time prolonged, blood phosphate increased, blood lactate increased.

Cardiac arrhythmias and pancreatitis have been reported. In adults and adolescents (≥ 12 years of age), liver toxicity may occur following ingestion of doses greater than 7.5-10 g over a period of 8 hours or less. Fatal events are infrequent (less than 3-4% of untreated cases) and have been reported rarely in overdoses of less than 15 g. In children (Table n.2: Expected events for acute liver failure associated with paracetamol overdose

SOC	Reporting of suspected adverse reactions
Infections and infestations	Sepsis, fungal infection, bacterial infection
Pathologies of the hemolymphopoietic system	Disseminated intravascular coagulation, coagulopathy, thrombocytopenia.
Metabolism and nutrition disorders	Hypoglycemia, hypophosphataemia, metabolic acidosis, lactic acidosis.
Pathologies of the nervous system	Coma (with paracetamol or multiple drug overdose), encephalopathy, cerebral edema.
Heart pathologies	Cardiomyopathy.
Vascular pathologies	Hypotension.
Respiratory, thoracic and mediastinal disorders	Respiratory insufficiency.
Gastrointestinal pathologies	Pancreatitis, gastrointestinal bleeding.
Kidney and urinary pathologies	Acute renal failure with tubular necrosis.
General disorders and administration site conditions	Multi-organ failure.

Pseudoephedrine. As with other sympathomimetic agents, symptoms of an overdose may include nausea, vomiting, sympathomimetic symptoms including central nervous system stimulation, irritability, agitation, insomnia, tremors, anxiety, convulsions, palpitations, tachycardia, hypertension, reflex bradycardia, difficulty urinating, hallucinations, hypertonicity, hyperreflexia, mydriasis, hypokalaemia. Other effects may include arrhythmia, hypertensive crisis, intracelebral haemorrhage, myocardial infarction, psychosis, rhabdomyolysis, ischemic intestinal infarction. If necessary, support breathing and control convulsions, perform gastric lavage and, if necessary, catheterize the patient. In the event of an overdose, the pseudoephedrine contained in ACTIGRIP DAY AND NIGHT can cause a stroke. The elimination of pseudoephedrine can be accelerated by acid diuresis or dialysis. Diphenhydramine. . Mild to moderate symptoms of an overdose include: somnolence, hyperpyrexia and anticholinergic effects (mydriasis, hot flushes, fever, dry mouth, urinary retention, reduced borborygmi). tachycardia, mild hypertension, nausea and vomiting which are common in the presence of overdose. Agitation, confusion and hallucinations can develop with moderate intoxication. With very high doses, and especially in children, symptoms include: excitement, insomnia, nervousness, tremors and epileptic convulsions. Severe symptomsEffects may include delirium, psychosis, convulsions, coma, hypotension, cardiovascular collapse, QRS widening, and ventricular arrhythmias including torsades de pointes, but are generally only reported in adults after large ingestions. Rhabdomyolysis and renal failure may rarely develop in patients with prolonged agitation, coma, or seizures. Death can occur due to respiratory failure or circulatory collapse. Treatment of an overdose is symptomatic and supportive. Measures to promote rapid gastric emptying (such as vomiting or gastric lavage) and, in case of acute poisoning, the intake of activated charcoal are useful. Intravenous administration of physostigmine may antagonize anticholinergic symptoms. Emergency procedure. In case of taking an excessive dose of ACTIGRIP DAY & NIGHT: § take the patient immediately to the hospital; § take a blood sample to determine the initial plasma levels of paracetamol; § perform a gastric lavage; § acidify the urine, administering ammonium chloride to increase the elimination of pseudoephedrine. The treatment of overdose usually involves the administration, as soon as possible, of the antidote N-acetylcysteine orally or intravenously, if possible before the tenth hour after intake. Symptomatic treatment.

The medicine is contraindicated in case of confirmed and presumed pregnancy, and during breastfeeding. There are no adequate and well-controlled clinical studies in pregnant or lactating women for the combination of diphenhydramine, paracetamol and pseudoephedrine.

Pregnancy

: Diphenhydramine crosses the placenta and is excreted in breast milk, but levels have not been reported. Paracetamol crosses the placenta.

Feeding time

: Paracetamol, pseudoephedrine and diphenhydramine are secreted in breast milk; therefore, ACTIGRIP DAY & NIGHT is contraindicated during breastfeeding. Paracetamol is excreted in breast milk in low concentrations (0.1% to 1.85% of the dose ingested by the mother). Pseudoephedrine is distributed in breast milk; Up to 0.6% of a single 60 mg dose can be detected in breast milk over a 24-hour period. There are no data on plasma protein binding in humans. Data from a study of 8 nursing mothers taking 60 mg of pseudoephedrine every 6 hours suggest that approximately 4.3% of the maximum daily dose (240 mg) could be made available to the infant by the nursing mother.

Source: Farmadati