Excipient guideline update (update annex 2017)

Excipient guideline update (Updated annex 2017)

Aspirin 300mg Effervescent Tablets – 1410/37/1
15131
www.medicines.ie

(Inserted Text; Deleted Text)

4.2          Posology and method of administration

Poslogy:

Oral

Tablets must be dissolved in water. The tablets should preferably be taken after meals.

Dosage regimen

…

4.4          Special warnings and precautions for use

Aspirin should be used with particular caution in the following cases:

·         Hypersensitivity to analgaesicsanalgesics / anti-inflammatory agents / anti-rheumatics in the presence of other allergies,

·         History of gastro-intestinal ulcers including chronic or recurrent ulcer disease or history of gastro-intestinal bleedings,

·         With concomitant treatment with anticoagulants (see interactions with other medicinal products and other forms of interaction),

·         Patients with impaired renal function or patients with impaired cardiovascular circulation (e.g. renal vascular disease, congestive heart failure, volume depletion, major surgery, sepsis or major hemorrhagic events), since acetylsalicylic acid may further increase the risk of renal impairment and acute renal failure

...

4.5          Interaction with other medicinal products and other forms of interactions

…

Combinations requiring precautions for use:

…

Anticoagulants, thrombolytics/other inhibitors of platelet aggregation/haemostasis

…

4.6          Fertility, pregnancy and lactation.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fœtal development. Data from epidemiological studies raise concern about an increased risk of mis¬carriage and of malformations after the use of a prostaglandin synthesis inhibitor in early preg¬nan¬cy. The risk is believed to increase with dose and duration of therapy. Available data do not support any association between intake of acetylsalicylic acid and an increased risk for miscarriage. For acetyl¬salicylic acid the available epidemiological data regarding malformation are not consistent, but an increased risk of gastroschisis could not be excluded. A prospective study with exposure in ear¬ly pregnancy (1st-4th month) of about 14,800 mother-child pairs has not yielded any association with an elevated rate of malformations. Animal studies have shown reproductive toxicity (see See Section 5.3 Preclinical Safety Data).

…

4.8          Undesirable effects.

The listed adverse drug reactions are based on spontaneous reports, thus an organisation according to CIOMS III categories of frequency is not possible.

Blood and lymphatic system disorders

Haemorrhagic anaemia[i], iron deficiency anaemia[i] with the respective laboratory and clinical signs and symptoms. Haemolysis[ii], haemolytic anaemia[i]

Cardiac disorders

Cardio-respiratory distress [iii]

…

Renal and urinary disorders

Urogenital haemorrhage, renal impairment [iv], renal failure acute[iv]

…

4.9          Overdose

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5.1          Pharmacodynamic properties

Pharmacotherapeutic group: Nervous system, other analgaesicsanalgesics and antipyretics. ATC-Code: N02BA01

…

5.3          Preclinical safety data

…

The preclinical safety profile of acetylsalicylic acid is well documented.

In animal studies, salicylates caused kidney damage at high dosages but no other organic lesions. Acetylsalicylic acid has been extensively studied in vitro and in vivo for mutagenicity; no relevant evidence of a mutagenic potential was found. The same applies to carcinogenicity studies.

Salicylates have exhibited teratogenic effects in animal studies and a number of different species. Implantation disorders, embryotoxic and foetotoxic effects and impairment of learning ability in the offspring after prenatal exposure have been described.

10           Date of revision of the text

April 2015July 2015

4.8 Undesirable effects

…

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

10. DATE OF REVISION OF THE TEXT

June 2012April 2015

Section 4.2:

In the sub-section "Adults" the sentence "Aspirin must not be taken for longer than 3-5 days without consulting your doctor." was added.

Section 4.4:

The bullet point "impaired renal function" was changed to "  patients with impaired renal function or patients with impaired cardiovascular circulation (e.g renal vascular disease, congestive heart failure, volume depletion, major surgery, sepsis or major hemorrhagic events), since acetylsalicylic acid may further increase the risk of renal impairment and acute renal failure,"

The paragraph "In patients suffering from severe glucose-6-phosphate dehydrogenase (G6PD) deficiency, acetylsalicylic acid may induce haemolysis or haemolytic anaemia. Factors that may increase the risk of haemolysis are high dosage, fever, or acute infections, for example." was added.

Section 4.6:

 The sentence "the mother and the child, at the end of pregnancy, to: " was changed to "Prostaglandin synthesis inhibitors may expose the mother and the child, at the end of pregnancy, to"

Section 4.8:

The whole section was replaced with:

The listed adverse drug reactions are based on spontaneous reports, thus an organisation according to CIOMS III categories of frequency is not possible.

Blood and lymphatic system disorders

Haemorrhagic anaemia[i], iron deficiency anaemia[i] with the respective laboratory and clinical signs and symptoms. Haemolysis[ii], haemolytic anaemia[i]

Cardiac disorders

Cardio-respiratory distress [iii]

Ear and labyrinth disorders

Tinnitus

Gastrointestinal disorders

Dyspepsia, gastrointestinal pain, abdominal pain, gingival bleeding, gastrointestinal inflammation, gastrointestinal ulcer, gastrointestinal haemorrhage, gastrointestinal ulcer perforation with the respective laboratory and clinical signs and symptoms.

Hepatobiliary disorders

Liver disorder, transaminases increased

Immune system disorders

Hypersensitivity, drug hypersensitivity, allergic edema and angioedema, anaphylactic reaction, anaphylactic shock with respective laboratory and clinical manifestations

Injury, poisoning and procedural complications

See overdose section

Nervous system disorders

Cerebral and intracranial haemorrhage, dizziness

Renal and urinary disorders

Urogenital haemorrhage, renal impairment [iv], renal failure acute[iv]

Respiratory, thoracic and mediastinal disorders

Epistaxis, analgaesic asthma syndrome, rhinitis, nasal congestion

Skin and subcutaneous tissue disorders

Rash, urticaria, pruritus

Vascular disorders

Haemorrhage, operative haemorrhage, haematoma, muscle haemorrhage

Section 5.1

The sentence "generally high doses of 4 to 8g daily in divided doses are used for these disorders" was removed from the fourth paragraph of this section.

Section 10

Date of revision of text changed from Novemer 2009 to June 2012

Section 4.3 (Contraindications) now reads:

Aspirin must not be used in the following cases:

·      hypersensitivity to acetylsalicylic acid or other salicylates, or to any other compo­nents of the product,

·       a history of asthma induced by the administration of salicylates or substances with a similar action, notably non-steroidal anti-inflammatory drugs,

·      acute gastrointestinal ulcers,

·      hemorrhagic diathesis,

·      severe renal failure,

·      severe hepatic failure,

·      severe cardiac failure,

·       combination with methotrexate at doses of 15 mg/week or more (see interac­tions with other medicinal products and other forms of interaction),

·       last trimester of pregnancy.

Section 4.4 (Special warnings and precautions for use) now reads:

Aspirin should be used with particular caution in the following cases:

·       hypersensitivity to analgesics / anti-inflammatory agents / anti-rheumatics and in the presence of other allergies,

·       history of gastro-intestinal ulcers including chronic or recurrent ulcer disease or history of gastro-intestinal bleedings,

·       with concomitant treatment with anticoagulants (see interactions with other me­dicinal products and other forms of interaction),

·       impaired renal function,

·       impaired hepatic function.

Acetylsalicylic acid may precipitate bronchospasm and induce asthma attacks or other hypersensitivity reactions. Risk factors are pre-existing asthma, hay fever, nasal polyps, or chronic respiratory disease. This also applies to patients exhibiting allergic reactions (e.g. cutaneous reactions, itching, urticaria) to other substances.

Due to its inhibitory effect on platelet aggregation which persists for several days after administration, acetylsalicylic acid may lead to an increased bleeding tendency dur­ing and after surgical operations (including minor surgeries, e.g. dental extractions).

At low doses, acetylsalicylic acid reduces the excretion of uric acid. This can possibly trigger gout attacks in predisposed patients.

Undesirable effects may be reduced by using the minimum effective dose for the shortest possible duration.  Patients treated with NSAIDs long-term should undergo regular medical supervision to monitor for adverse events.

Elderly patients are particularly susceptible to the adverse effects of NSAIDs.  Prolonged use of NSAIDs in the elderly is not recommended. Where prolonged therapy is required, patients should be reviewed regularly.

There is possible association between aspirin and Reye’s syndrome when given to children. Reye’s syndrome is a very rare disease, which affects the brain and liver, and can be fatal. For this reason aspirin should not be given to children and adolescents aged under 16 years unless specifically indicated.

Prolonged use, except under medical supervision, can be harmful.

If symptoms persist, the physician should be consulted.

This medicinal product contains 150 mg sodium per effervescent tablet. To be taken into consideration by patients on a controlled sodium diet.

Section 4.5 (Interaction with other medicinal products and other forms of interactions) now reads:

Contra-indicated Interactions:

Methotrexate used at doses of 15 mg/week or more:

Increased hematological toxicity of methotrexate (decreased renal clearance of meth­otrexate by anti-inflammatory agents in general and displacement of methotrexate from its plasma protein binding by salicylates) (see Section 4.3 Contraindications).

Combinations requiring precautions for use:

Methotrexate, used at doses of less than 15 mg/week:

Increased hematological toxicity of methotrexate (decreased renal clearance of methotrexate by anti‑inflammatory agents in general and displacement of methotrexate from its plasma protein binding by salicylates).

Anticoagulants, thrombolytics/other inhibitors of platelet aggrega­tion/hemostasis:

Increased risk of bleeding.

Other non‑steroidal anti‑inflammatory drugs with salicylates at higher doses       

Increased risk of ulcers and gastrointestinal bleeding due to synergistic effect.

Ibuprofen:

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see Section 5.1).

Selective Serotonin Re-uptake Inhibitors (SSRIs):

Increased risk of upper gastrointestinal bleeding due to possibly synergistic effect

Digoxin:

Plasma concentrations of digoxin are increased due to a decrease in renal excretion.

Antidiabetics, e.g. insulin, sulphonylureas:

Increased hypoglycemic effect by high doses of acetylsalicylic acid via hypoglycemic action of acetylsalicylic acid and displacement of sulfonylurea from its plasma protein binding.

Diuretics in combination with acetylsalicylic acid at higher doses:

Decreased glomerular filtration via decreased renal prostaglandin synthesis.

Systemic glucocorticoids, except hydrocortisone used as replacement therapy in Addison's disease:

Decreased blood salicylate levels during corticosteroid treatment and risk of salicy­late overdose after this treatment is stopped via increased elimination of salicylates by corticosteroids.

Angiotensin converting enzyme inhibitors (ACE) in combination with acetyl­salicylic acid at higher doses:

Decreased glomerular filtration via inhibition of vasodilatory prostaglandins. Furthermore, decreased antihypertensive effect.

Valproic acid:

Increased toxicity of valproic acid due to displacement from protein binding sites.

Alcohol:

Increased damage to gastro-intestinal mucosa and prolonged bleeding time due to additive effects of acetylsalicylic acid and alcohol.

Uricosurics such as benzbromarone, probenecid:

Decreased uricosuric effect (competition of renal tubular uric acid elimination).

Section 4.6 (Pregnancy and lactation) now reads:

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/fœtal development. Data from epidemiological studies raise concern about an increased risk of mis­carriage and of malformations after the use of a prostaglandin synthesis inhibitor in early preg­nan­cy. The risk is believed to increase with dose and duration of therapy. Available data do not support any association between intake of acetylsalicylic acid and an increased risk for miscarriage. For acetyl­salicylic acid the available epidemiological data regarding malformation are not consistent, but an increased risk of gastroschisis could not be excluded. A prospective study with exposure in ear­ly pregnancy (1st-4th month) of about 14,800 mother-child pairs has not yielded any association with an elevated rate of malformations. Animal studies have shown reproductive toxicity (see Section 5.3 Preclinical Safety Data).

During the first and second trimester of pregnancy, acetyl salicylic acid containing drugs should not be given unless clearly necessary. If acetylsalicylic acid containing drugs are used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

·      cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);

·      renal dysfunction, which may progress to renal failure with oligo-hydroamniosis;

the mother and the child, at the end of pregnancy, to:

·      possible prolongation of bleeding time, an anti-aggregating effect which may occur even after very low doses

·      inhibition of uterine contractions resulting in delayed or prolonged labour

Consequently, acetylsalicylic acid is contraindicated during the third trimester of pregnancy.

Lactation

Salicylate and its metabolites pass into breast milk in small quantities.

Since no adverse effects on the infant have been observed so far after occasional use, interruption of breast-feeding is usually unnecessary. However, on regular use or on intake of high doses, breast feeding should be discontinued early.

Section 4.8 (Undesirable effects) now reads:

Upper and lower gastrointestinal tract disorders such as common signs and symptoms of dyspepsia, gastrointestinal and abdominal pain, rarely gastrointestinal in­flammation, gastrointestinal ulcer, potentially but very rarely leading to gastrointesti­nal ulcer hemorrhage and perforation, with the respective laboratory and clinical signs and symptoms.

Due to its inhibitory effect on platelets, acetylsalicylic acid may be associated with an increased risk of bleeding. Bleedings, such as perioperative hemorrhage, hemato­mas, epistaxis, urogenital bleedings, gingival bleedings, have been observed. Rare to very rare serious bleedings, such as gastrointestinal tract hemorrhage, cerebral hemor­rhage (especially in patients with uncontrolled hypertension and/or on concomi­tant antihemostatic agents), which in single cases may be potentially life-threat­ening, have been reported.

Hemorrhage may result in acute and chronic posthemorrhagic anemia/iron-deficiency anemia (due to e.g. occult microbleeding) with respective laboratory and clinical signs and symptoms, such as asthenia, pallor, hypoperfusion.

Hypersensitivity reactions with respective laboratory and clinical manifestations in­clude asthma syndrome, mild to moderate reactions potentially affecting skin, respiratory tract, gastrointestinal tract, and cardiovascular system, including symp­toms such as rash, urticaria, edema, pruritus, rhinitis, nasal congestion, cardio-respiratory distress, and very rarely, severe reactions, including anaphylactic shock.

Transient hepatic impairment with increase in liver transaminases has very rarely been reported.

Dizziness and tinnitus have been reported, which may be indicative of an overdose.

Section 4.9 (Overdose) now reads:

Salicylate toxicity (> 100 mg/kg/day over 2 days may produce toxicity) may result from chronic, therapeutically acquired, intoxication, and from, potentially life-threat­ening, acute intoxications (overdose), ranging from accidental ingestions in children to incidental intoxications.

Chronic salicylate poisoning can be insidious as signs and symptoms are non-spe­cific. Mild chronic salicylate intoxication, or salicylism, usually occurs only after re­peated use of large doses. Symptoms include dizziness, vertigo, tinnitus, deafness, sweating, nausea and vomiting, headache, and confusion, and may be controlled by reducing the dosage. Tinnitus can occur at plasma concentrations of 150 to 300 mi­crograms/mL. More serious adverse events occur at concentrations above 300 mi­crograms/mL.

The principle feature of acute intoxication is severe disturbance of the acid-base balance, which may vary with age and severity of intoxication. The most common presentation for a child is metabolic acidosis. The severity of poisoning cannot be estimated from plasma concentration alone. Absorption of acetylsalicylic acid can be delayed due to reduced gastric emptying, formation of concretions in the stomach, or as a result of ingestion of enteric-coated preparations. Management of acetylsalicylic acid intoxication is determined by its extent, stage and clinical symptoms and ac­cording to standard poisoning management techniques. Predominant measures should be the accelerated excretion of the drug as well as the restoration of the electrolyte and acid-base metabolism.

Due to the complex pathophysiologic effects of salicylate poisoning, signs and symptoms/investigational findings may include:

Section 5.1 (Pharmacodynamic properties) should now read:

Pharmacotherapeutic group: Nervous system, other analgesics and antipyretics.  ATC-Code: N02BA01

Acetylsalicylic acid belongs to the group of acidic nonsteroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory properties. Its mechanism of action is based on irreversible inhibition of cyclo-oxygenase enzymes involved in prostaglandin synthesis.

Acetylsalicylic acid in oral doses of in general 0.3 to 1.0 g is used for the relief of pain and in minor febrile conditions, such as colds or influenza, for the reduction of tem­perature and relief of the joint and muscle pains.

It is also used in acute and chronic inflammatory disorders such as rheumatoid arthri­tis, osteoarthritis, and ankylosing spondylitis. Generally high doses of 4 to 8 g daily in divided doses are used for these disorders.

Acetylsalicylic acid also inhibits platelet aggregation by blocking thromboxane A₂ synthesis in platelets. Thus, it is used for various vascular indications at doses of in general 75 to 300 mg daily.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

Section 5.2 (Pharmacokinetic properties) should now read:

Following oral administration, acetylsalicylic acid is absorbed rapidly and completely from the gastro-intestinal tract. During and after absorption acetylsalicylic acid is con­verted into its main active metabolite, salicylic acid. Maximal plasma levels are reached after 10 - 20 minutes for acetylsalicylic acid and after 0.3-2 hours for salicylic acid, respectively.

Both acetylsalicylic acid and salicylic acid are extensively bound to plasma proteins and are rapidly distributed throughout the body. Salicylic acid passes into breast milk and crosses the placenta.

Salicylic acid is eliminated predominantly by hepatic metabolism. Its metabolites are salicyluric acid, salicylic phenolic glucuronide, salicylacyl glucuronide, gentisic acid, and gentisuric acid.

The elimination kinetics of salicylic acid is dose-dependent, as metabolism is limited by liver enzyme capacity. The elimination half-life therefore varies from 2 to 3 hours after low doses to up to about 15 hours at high doses. Salicylic acid and its metabo­lites are excreted mainly via the kidneys.

Section 5.3 (Preclinical Safety data) should now say:

The preclinical safety profile of acetylsalicylic acid is well documented.

In animal studies, salicylates caused kidney damage at high dosages but no other organic lesions. Acetylsalicylic acid has been extensively studied in vitro and in vivo for mutagenicity; no relevant evidence of a mutagenic potential was found. The same applies to carcinogenicity studies.

Salicylates have exhibited teratogenic effects in animal studies and a number of different species. Implantation disorders, embryotoxic and fetotoxic effects and impairment of learning ability in the offspring after prenatal exposure have been described.

There is some evidence that drugs which inhibit cyclo-oxygenase / prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

Section 7: MA holder is now Bayer Ltd.

Section 8: MA number is now 1410/37/1