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Prescribing information

Aspirin C

1. Name of drug product

Aspirin® C
400 mg acetylsalicylic acid
240 mg, ascorbic acid

Effervescent tablet

2. Qualitative and quantitative composition

One effervescent tablet contains: 400 mg acetylsalicylic acid (Ph-Eur.)
and 240 mg ascorbic acid

Complete list of excipients see section 6.1.

3. Presentation
Effervescent tablet

4. Clinical data

4.1 Indications
- Pain relief
- Fever reduction
- Antirheumatic treatment

Please note the instructions for children and adolescents (see section
4.4).

4.2 Dosage, and method of administration

Dosage

The usual dose is:

Age or Single dose Total daily dose

1 effervescent 3 effervescent
Children 9-12 tablet (equivalent tablets (equivalent to
to 400 mg 1,200 mg
acetylsalicylic acid acetylsalicylic acid
and 240 mg and 720 mg ascorbic
ascorbic acid) acid)
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1-2 effervescent 8 effervescent

Adolescents and tablets tablets (equivalent to
adults (equivalent to 400- 3,200 mg
800 mg acetylsalicylic acid
acetylsalicylic acid and 1 mg ascorbic
and 240-480 mg acid)
ascorbic acid)

The single dose can be taken at intervals of 4 to 6 hours if necessary.

Description of application

The tablets are taken dissolved in liquid.

Do not take on an empty stomach.

Aspirin C must not be taken for more than 4 days without consulting a
physician.

4.3 Contraindications
- Hypersensitivity to acetylsalicylic acid, other salicylates, ascorbic acid
or to any of the excipients listed in section 6.1,
- History of asthma attacks caused by salicylates or substances with
similar effects, especially nonsteroidal anti-inflammatory drugs;
- Acute gastrointestinal ulcers;
- Haemorrhagic diathesis;
- Liver and kidney failure;
- Severe, non-stabilized heart failure;
- Concomitant treatment with methotrexate at doses of 15 mg/week
or more (see section 4.5);
- Last trimester of pregnancy (see section 4.6).

4.4 Special Warnings and precautions for use

Acetylsalicylic acid
- Hypersensitivity to other analgesics / anti-inflammatory or
antirheumatic drugs or other allergenic substances(see section 4.3);
- Existing allergies (e.g. skin reactions, itching, nettle rash), asthma,
hay fever, nasal polyps or chronic respiratory tract infections;
- Concomitant treatment with anticoagulants;
- history of gastrointestinal ulcers or -bleeding;
- Impaired liver function;
- 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;
- Before surgery (including minor surgery such as dental extractions);
bleeding tendency could be increased;
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- Patients suffering from severe glucose-6-phosphate dehydrogenase

(G6PD) deficiency: acetylsalicylic acid may induce hemolysis or
hemolytic anemia. Factors that may increase the risk of hemolysis
are e.g. high dosage, fever or acute infections.

Ascorbic acid
- Calcium oxalate urolithiasis
- Iron storage diseases (thalassaemia, haemochromatosis)

What other precautions must be taken?

One effervescent tablet contains 20.3 mmol (466.4 mg) sodium. This
must be taken into account by patients on a controlled sodium (low-
sodium/low-salt) diet.

Long-term consumption of analgesics can cause headaches which, if

treated with more analgesics, can in turn lead to persistent headaches..

Habitual use of analgesics can lead to permanent kidney damage with

the risk of kidney failure (analgesic nephropathy). The risk increases
significantly when several different analgesics are taken concomitantly.

At low doses acetylsalicylic acid reduces the excretion of uric acid. This
may cause a gout attack in patients which already tend to a decreased
renal excretion.

Children or adolescents
Acetylsalicylic acid should not be taken by children or adolescents with
feverish illnesses unless they have been instructed to do so by a doctor
and other therapeutic measures have failed. Prolonged vomiting in
conjunction with such illnesses could be a sign of Reye’s syndrome, a
very rare but life-threatening disease which requires immediate medical
attention.

4.5 Interactions with other medical products s and other forms of

interaction

Enhanced effects ranging up to an increased risk of side effects:

- Anticoagulants / thrombolytics: Acetylsalicylic acid can increase the
risk of bleeding when taken before thrombolytic treatment. Attention
should therefore be paid for signs of external or internal bleeding in
patients who are scheduled to undergo thrombolytic treatment.
- Platelet aggregation inhibitors, e.g. ticlopidine, clopidogrel:
increased risk of bleeding;
- Other nonsteroidal analgesics / anti-inflammatory (at dosages of 3 g
acetylsalicylic acid per day and above): increased risk of
gastrointestinal ulcers and -bleeding;
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- Systemic glucocorticoids (with the exception of hydrocortisone as

replacement therapy for Addison’s disease): increased risk of
gastrointestinal side effects;
- Alcohol: increased risk of gastrointestinal ulcers and -bleeding;
- Digoxin: increase in plasma levels;
- Antidiabetics: the blood glucose level can be reduced;
- Methotrexate: decrease in elimination and displacement from protein
binding by salicylates;
- Valproic acid: displacement from protein binding by salicylate;
- Selective Serotonin Re-uptake inhibitors (SSRIs): increased risk of
gastrointestinal bleeding due to synergetic effects.

Weakening of effects:
- Diuretics (at dosages of 3 g acetylsalicylic acid per day and above);
- ACE inhibitors (at dosages of 3 g acetylsalicylic acid per day and
above);
- Uricosuric agents (e.g. probenecid, benzbromarone)
- Deferoxamine: Concurrent use with ascorbic acid may enhance tissue
iron toxicity, especially in the heart, causing cardiac decompensation.

4.6 Fertility, Pregnancy and lactation

Pregnancy
Inhibition of prostaglandin synthesis may adversely affect the
pregnancy and/or the embryo/foetal 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.
For acetylsalicylic acid overall the available epidemiological data suggest
an increased risk of gastroschisis.
Animal studies have shown reproductive toxicity (see section 5.3).
During the first and second trimester of pregnancy, acetyl salicylic acid
should not be given unless clearly necessary. If acetyl salicylic acid is
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
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Consequently, acetyl salicylic acid is contraindicated during the third

trimester of pregnancy. (see section 4.3).

Lactation
Salicylates 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.

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

4.7 Effects on the ability to drive and use machines

Acetyl salicylic acid does not influence the ability to drive and to use
machines

4.8. Side effects

From Acetylsalicylic acid
The following adverse effects comprise all reported side effects following
treatment with acetylsalicylic acid, including those following long-term,
high-dose therapy in rheumatism patients. The incidence figures for
events that go beyond isolated cases are based on short-term use of
daily doses of not more than 3 g acetylsalicylic acid.

The following incidence rating is used to evaluate the frequency of side

effects:

Very common: ≥ 1/10

Common: ≥ 1/100,  1/10
Uncommon: ≥ 1/1.000,  1/100
Rare: ≥ 1/10.000,  1/1.000
Very rare:  1/10.000
Unknown: Frequency could not be estimated by given data

Blood and lymphatic system disorders:

Rare to very rare serious bleedings, such as cerebral hemorrhage
(especially in patients with uncontrolled hypertension and/or on
concomitant treatment with anticoagulants), which in single cases may
be potentially life-threatening, have been reported.
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Hemolysis and hemolytic anemia in patients with severe forms of

glucose-6-phosphate dehydrogenase (G6PD) deficiency have been
reported.
Bleeding, e.g. nosebleeds, bleeding gums or skin bleeding, or bleeding
of the genitourinary system with possibly prolongation of the bleeding
time (see section 4.4). This effect can persist for 4 to 8 days after use.

Gastrointestinal system disorders:

Common:
Gastrointestinal disorders such as heartburn, nausea, vomiting,
abdominal pain.
Rare:
Gastrointestinal ulcers which in very rare cases can lead to perforation.
Gastrointestinal bleeding which in very rare cases can lead to iron
deficiency anaemia.
Gastrointestinal inflammations.

Nervous system disorders:

Headache, dizziness, impaired hearing ability; tinnitus and mental
confusion can be signs of an overdose (see section 4.9).

Skin and subcutaneous tissue disorders:

Uncommon:
Hypersensitivity reactions like skin reactions.
Rare:
Hypersensitivity reactions like severe skin reactions (up to erythema
exsudativum multiforme).

Immune system disorders:

Rare:
Hypersensitivity reactions of the respiration tract, the gastrointestinal
tract and the cardiovascular system, especially in asthmatic.
Possibly with: drop in blood pressure, attacks of dyspnoea, rhinitis,
nasal congestion, anaphylactic shock or angioneurotic oedema.

Liver- and biliary disorders:

Very rare:
Increases in liver function tests
Renal and urinary disorders:
Renal impairment and acute renal failure have been reported.

Ascorbic acid (Vitamin C)

The side effects listed below on "spontaneous reports", so that a sort of
frequency information is not possible based (frequency not known).

Immune system disorders

Hypersensitivity reactions, allergic reactions and anaphylactic shock

Gastrointestinal disorders
Diarrhea, nausea, vomiting, gastrointestinal pain, abdominal pain
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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.
Any suspected adverse events should be reported to the Ministry of
Health according to the National Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formTyp
[email protected]).

4.9 Overdosage
Intoxication is more likely in elderly patients and, in particular, infants
(therapeutic overdosage or accidental intoxication can be fatal for
them).

Symptomatology:
Moderate intoxication:
Tinnitus, hearing disorders, diaphoresis, nausea, vomiting, headache
and vertigo are reported in all cases of overdosage and can be
eliminated by reducing the dose.

Severe intoxication:
Fever, hyperventilation, ketosis, respiratory alkalosis, metabolic
acidosis, coma, cardiovascular shock, respiratory failure, severe
hypoglycaemia.

Emergency treatment:
- Immediate admission to hospital;
- Gastric lavage and administration of activated carbon, monitoring of
the acid-base balance;
- Alkaline diuresis to attain a urine pH of between 7.5 and 8;
increased alkaline diuresis must be considered if the plasma
salicylate concentration exceeds 500 mg/l (3.6 mmol/l) in adults or
300 mg/l (2.2 mmol/l) in children;
- Optionally haemodialysis in cases of severe intoxication;
- Fluid loss must be compensated;
- Symptomatic treatment.

Single cases of acute and chronic ascorbic acid overdoses are reported
in the literature. Ascorbic acid overdose may result in oxidative
hemolysis in patients with glucose-6-phosphate dehydrogenase
deficiency, disseminated intravascular coagulation, and significantly
elevated levels of serum and urinary oxalate levels.
Increased levels of oxalate concentration have been shown to lead to
calcium oxalate deposits in dialysis patients.
Additionally, there are several reports which showed that large doses of
vitamin C both orally and intravenously can provoke calcium oxalate
deposits, calcium oxalate crystalluria in patients who have a
predisposition for increased crystal aggregation, tubulointerstitial
nephropathy, and acute renal failure as a result of calcium oxalate
crystals.
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5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nervous system, other analgesics and
antipyretics, salicylic acid and derivate
ATC class: N02BA 01

Acetylsalicylic acid belongs to the class of acid-forming nonsteroidal

anti-inflammatory drugs with analgesic, antipyretic and anti-
inflammatory properties. Its mechanism of action is based on
irreversible inhibition of cyclooxygenase enzymes involved in
prostaglandin synthesis.
Acetylsalicylic acid is used at oral doses of between 0.3 and 1.0 g to
treat mild to moderate pain and fever, e.g. with colds or ’flu, to lower
temperatures and to treat joint and muscle pain.
It is also used to treat acute and chronic inflammatory diseases such as
rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.
Acetylsalicylic acid also inhibits platelet aggregation by blocking the
synthesis of thromboxane A2 in the platelets. To this end, doses of 75
to 300 mg daily are used for various cardiovascular indications.
The water-soluble vitamin ascorbic acid is part of a protective system of
the organism against oxygen radicals and other oxidants of endogenous
and exogenous origin which also play a particular role in the
inflammatory process and in leukocyte function. Both in vitro and ex
vivo experiments indicate that ascorbic acid has a positive effect on the
leukocytic immune response in humans.
Ascorbic acid is essential for the synthesis of the intracellular basic
substance (muco-polysaccharides) which, together with the collagen
fibers, is responsible for sealing the capillary walls.
Clinical studies have yielded evidence that using acetylsalicylic acid and
ascorbic acid in combination provides protection against acetylsalicylic
acid-induced stomach lesions and oxidative stress.

5.2 Pharmacokinetic properties

Acetylsalicylic acid is absorbed rapidly and completely from the
gastrointestinal tract after oral administration. Acetylsalicylic acid is
converted into its main metabolite salicylic acid during and after
absorption. Peak plasma levels of acetylsalicylic acid and salicylic acid
are achieved after 10-20 min and 0.3-2 h respectively.
Both acetylsalicylic acid and salicylic acid are bound largely to plasma
proteins and rapidly distributed to all parts of the body. Salicylic acid
passes into breast milk and crosses the placental barrier.
Salicylic acid is eliminated predominantly by metabolization in the liver;
the metabolites are salicyluric acid, salicyl phenolic glucuronide, salicylic
acyl glucuronide, gentisic acid and gentisuric acid.
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The elimination kinetics of salicylic acid are dose-dependent, as

metabolism is limited by the liver enzymes capacity. The elimination
half-life therefore varies and lies between 2 and 3 h at low doses and up
to about 15 h at high doses. Salicylic acid and its metabolites are
excreted primarily via the renal route.

Absorption of ascorbic acid (concentration-dependent in the proximal

section of the small intestine) is limited. As the single dose increases,
bioavailability decreases (60-75% after 1 g, 16% after 12 g). The
unabsorbed fraction is broken down by the flora in the large bowel,
mainly into CO2 and organic acids. In healthy adults, the maximum
metabolic turnover of 40-50 mg/day is reached at plasma
concentrations of 0.8-1.0 mg/day. At extremely high oral doses, plasma
concentrations of up to 4.2 mg/dl are achievable in the short-term after
three hours. Under these conditions, ascorbic acid is excreted
predominantly (>80%) unchanged in the urine (half-life 2.9 hours). The
pool in the body following regular administration of approximately 180
mg/day is at least 1.5 g. Significant accumulation occurs in the pituitary
gland, adrenal glands, eye lenses and white blood cells.

5.3 Preclinical safety data

The preclinical safety profile of acetylsalicylic acid is well documented.
In animal tests salicylates caused kidney damage and gastrointestinal
ulcers. Acetylsalicylic acid has been adequately tested for mutagenicity
and carcinogenicity; no relevant evidence of a mutagenic or
carcinogenic potential was found.

Salicylates have been found to have teratogenic effects in a number of

animal species. There have been reports of implantation disturbances,
embryotoxic and fetotoxic effects, and disturbances of learning capacity
in the offspring after prenatal exposure.

6 Pharmaceutical data

6.1 List of exipients

Sodium hydrogen citrate, sodium hydrogen carbonate, anhydrous citric
acid, anhydrous sodium carbonate.

6.2 Incompatibilities
None

6.3 Shelf-life
36 months

6.4 Special storage instructions

Store below 25°C

6.5 Type and contents of container

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Blister
Original pack contains 10, 20 effervescent tablets
Not all pack sizes may be marketed.

6.6 Special precaution for disposal and other handling

No special requirements

7. Product license holder

Bayer Israel Ltd., 36 Hacharash St., Hod Hasharon 45240

8. Registration number
057 86 24955 00