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Section 4.3 Contraindications

The following text was deleted:

·          Use of codeine containing products is contraindicated in mothers who are breastfeeding unless prescribed by a doctor.

Section 4.4 Special warnings and special precautions for use

The following text was added:

·          Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the caucasian population may have this deficiency. However, if a patient is an ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the caucasian population may be ultra-rapid metabolisers.

Section 4.6 Fertility, pregnancy and lactation

The following text was added:

·          At normal therapeutic doses codeine and its active metabolites may be present in breast milk at very low doses and are unlikely to adversely affect the breast fed infant.

However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolites may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant.

If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

The following text was deleted:

·          In nursing mothers, who are ultra-rapid metabolisers of codeine, higher than expected serum and breast milk morphine levels can occur. Morphine toxicity in babies can cause excessive somnolence, hypotonia, miosis and difficulty breastfeeding or breathing. In severe cases respiratory depression and death can occur. In severe cases, naloxone may be appropriate to reverse the effects. The lowest effective dose should be used, for the shortest possible time.

Nursing mothers should be informed about carefully monitoring the infant during treatment for any signs and/or symptoms of morphine toxicity such as increased drowsiness or sedation, difficulty breastfeeding, breathing difficulties, miosis and decreased tone, and seeking immediate medical care if such symptoms or signs are noticed. The nursing mother should be informed about monitoring for signs and symptoms of maternal opioid toxicity as well. Should such signs/symptoms be noted in mother or baby, the mother should immediately stop taking all codeine containing medicines and seek medical advice.

Codeine containing products must not be used while breastfeeding unless prescribed by a doctor

4.3 Contraindications

Hypersensitivity to any of the constituents.  

Not to be taken by persons suffering from glaucoma. 

This product is not intended for the administration to children < 12 years of age.

Use of codeine containing products is contraindicated in mothers who are breastfeeding unless prescribed by a doctor.

Codeine is contraindicated in patients with acute asthma, respiratory depression, acute alcoholism, head injuries and raised intra-cranial pressure.

Severe hepatic insufficiency (Child-Pugh >9).

4.4 Special warnings and special precautions for use

If symptoms persist for more than three days consult your doctor as prolonged use without medical supervision could be harmful. 

Use with caution in the presence of renal or hepatic dysfunction.

Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped.

Due to hepatoxicity paracetamol must not be taken at higher doses or longer than recommended. Using longer than recommended may lead to severe hepatic sequela, such as hepatic cirrhosis. An acute or chronic overdose may lead to severe hepatoxicity, occasionally with lethal outcome (see section 4.9).

Patients suffering from hepatic diseases or infections affecting the liver such as viral hepatitis must consult their physician before taking paracetamol. For those patients hepatic function determinations may be required at periodic intervals during high-dose or long-term therapy, especially in patients with pre-existing hepatic disease.

Patients with hepatic insufficiency (Child-Pugh <9) should use paracetamol with caution.

An elevation of serum alanine aminotransferase (ALT) may occur during the administration of therapeutic doses of paracetamol.

Moderate alcohol intake and concomitant intake of paracetamol leads potentially to an increased risk of liver toxicity.

Patients suffering from renal diseases must consult their physician before taking paracetamol since dosing adjustment may be required. In case of severe renal insufficiency (creatinine clearance <10 ml/min) the physician has to assess critically the benefit/risk ratio of paracetamol use. Dosing adjustment and continuous monitoring must be ensured.

In general, a continuous use of paracetamol especially of paracetamol in combination with other analgesics may lead to permanent renal damage and the risk of renal failure (analgesic nephropathy).

The prolonged use of high doses may lead to liver and kidney damage. Conditions that increase the hepatic oxidative stress and decrease the hepatic glutathione reserve such as a variety of concomitant drugs, alcoholism, sepsis, or diabetes mellitus may place the patient at increased risk of hepatic toxicity to paracetamol at therapeutic doses.

Use of paracetamol by patients suffering from Gilbert syndrome may lead to more pronounced hyperbilirubinemia and clinical symptoms thereof such as jaundice. Thus, these patients should use paracetamol with caution.

Concomitant intake of other drugs containing paracetamol should be avoided.

Patients with hereditary glucose-6-phosphate-dehydrogenase deficiency should consult their physician before taking paracetamol (risk of hemolytic anaemia).

The hazards of paracetamol overdose are greater in those with non-cirrhotic alcoholic liver disease.

Immediate medical advice should be sought in the event of an overdose, even if the patient feels well, because of the risk of delayed, serious liver damage.

Care should be observed in administering the products to any patients whose condition may be exacerbated by opioids, those on concurrent CNS depressant drugs and those with inflammatory or obstructive bowel disorders.

In cases of renal insufficiency the rate of excretion of codeine and paracetamol metabolites may be reduced, and dosage schedules may need to be revised accordingly.

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of ‘Medication Overuse Headache’ should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Limited evidence suggests that individuals who are ultra-rapid metabolizer may convert codeine to its active metabolite, morphine, more rapidly and completely than other people. Patients may experience overdose symptoms such as extreme sleepiness, confusion, shallow breathing or severe constipation. This can also result in higher than expected serum and breast milk morphine levels (see “Pregnancy and Lactation”).

The elderly and patients under medical care (in particular those with urinary retention, or with cardiovascular, metabolic, gastrointestinal, liver or renal disease, or suffering from CNS disorders such as seizures) should consult a doctor before taking hyoscine hydrobromide.

Hyoscine hydrobromide may cause drowsiness. Children taking this medicine should not be left unattended.

Avoid alcoholic drink.

Do not exceed the stated dose.

This product should be kept out of the reach and sight of children.

4.5 Interactions with other medicinal products and other forms of interactions

Paracetamol:

Drugs leading to delayed gastric emptying, e.g. after use of propantheline or colestyramine, may lead to slower absorption of paracetamol and thus to a delay in the onset of action.

Drugs leading to accelerated gastric emptying, e.g. after use of metoclopramide or domperidone, may lead to faster absorption of paracetamol and thus to an acceleration in the onset of action.

Concomitant use of drugs which cause enzyme induction in the liver, e.g. certain hypnotics and antiepileptics (glutethimide, phenobarbital, phenytoin, carbamazepine etc.) or rifampicin may lead to liver damage even after paracetamol doses which would otherwise be harmless. In case of alcohol abuse, taking paracetamol, even in therapeutic dosages, may result in liver damage.

The effects of the following are intensified: combination with chloramphenicol may prolong the half-life of chloramphenicol and thus potentially increase its toxicity.

Paracetamol (or its metabolites) interferes with enzymes involved in vitamin K-dependent coagulation factor synthesis. Interactions between paracetamol and warfarin or coumarin derivatives may lead to an elevated international normalized ratio and an increased risk of bleeding. Patients on oral anticoagulants should therefore not take paracetamol for long periods without medical supervision.

Tropisetron and granisetron, 5-hydroxytryptamine type 3 antagonists, may totally inhibit the analgesic effect of paracetamol through a pharmacodynamic interaction.

Simultaneous use of paracetamol and AZT (zidovudine) increases the tendency towards a reduction in the white blood cell count (neutropenia). Paracetamol should therefore not be taken together with AZT, except on medical advice.

Codeine:

The effects of central nervous system depressants (including alcohol) may be potentiated by codeine.

Hyoscine hydrobromide:

The effects of hyoscine hydrobromide may be enhanced by other drugs with anticholinergic properties (including amantadine, classical antihistamines, phenothiazine antipsychotics and tricyclic antidepressants), therefore, combining these drugs with hyoscine should be avoided.

The sedative effect of hyoscine hydrobromide may be enhanced with alcohol or CNS depressants.

The reduction in gastric motility caused by hyoscine hydrobromide may affect the absorption of other drugs.

4.6 Pregnancy and lactation

Pregnancy

No data is available on the use of Feminax in human pregnancy.

Paracetamol:

Data from epidemiological studies on the therapeutic use of paracetamol gives rise to no concerns on possible undesirable effects regarding pregnancy, or fetal/neonatal development. Prospective data gathered regarding overdose in pregnancy showed no increased risk of malformations. In data from reproduction studies on oral use of paracetamol no evidence of malformations or fetotoxicity was found.

It is not recommended that paracetamol be used over a prolonged time period, in higher dosages or in combination with other drugs during pregnancy. The safe use under such conditions has not been confirmed.

Taking into account the risk/benefit ratio, paracetamol can be used throughout pregnancy, but it should be used only under a doctor’s advice.

Hyoscine hydrobromide:

The safety of hyoscine hydrobromide in pregnancy has not been established. It should only be used during pregnancy, particularly in the first trimester, if the expected benefit to the mother outweighs the potential risk to the developing foetus and on advice of a doctor.

Lactation

Paracetamol:

Paracetamol passes into breast milk in small quantities. Although no undesirable effects have been observed until now, paracetamol should be used during breastfeeding only upon doctor’s advice.

Codeine:

In nursing mothers, who are ultra-rapid metabolisers of codeine, higher than expected serum and breast milk morphine levels can occur. Morphine toxicity in babies can cause excessive somnolence, hypotonia, miosis and difficulty breastfeeding or breathing. In severe cases respiratory depression and death can occur. In severe cases, naloxone may be appropriate to reverse the effects. The lowest effective dose should be used, for the shortest possible time.

Nursing mothers should be informed about carefully monitoring the infant during treatment for any signs and/or symptoms of morphine toxicity such as increased drowsiness or sedation, difficulty breastfeeding, breathing difficulties, miosis and decreased tone, and seeking immediate medical care if such symptoms or signs are noticed. The nursing mother should be informed about monitoring for signs and symptoms of maternal opioid toxicity as well. Should such signs/symptoms be noted in mother or baby, the mother should immediately stop taking all codeine containing medicines and seek medical advice.

Codeine containing products must not be used while breastfeeding unless prescribed by a doctor.

Hyoscine hydrobromide:

Caution is required during lactation as small amounts of hyoscine hydrobromide may pass into breastmilk.

Section 4.8 has been changed entirely and now reads as follows: 

4.8 Undesirable effects

Paracetamol:

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

Blood and lymphatic system disorders

Changes in blood count including thrombocytopenia, thrombocytopenic purpura, leukopenia, and pancytopenia.

Gastrointestinal disorders

Nausea, vomiting, stomach discomfort, diarrhoea, and abdominal pain.

Hepatobiliary disorders

Hepatic impairment, hepatitis, as well as dose-dependent hepatic failure, hepatic necrosis (including with fatal outcome).

Chronic unapproved use may lead to hepatic fibrosis, hepatic cirrhosis including with fatal outcome (see sections 4.4. and 4.9.)

Immune system disorders

Allergic reactions, anaphylactic reaction, and anaphylactic shock.

Nervous system disorders

Dizziness, somnolence.

Renal and urinary disorders

Renal damage especially in case of overdose.

Respiratory, thoracic and mediastinal disorders

Bronchospasm and asthma including analgesic asthma syndrome.

Skin and subcutaneous tissue disorders

Rash, pruritus, urticaria, allergic edema and angioedema, acute generalized exanthematous pustulosis, fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis (including with fatal outcome).

Codeine:

Codeine may sometimes cause constipation. 

Hyoscine hydrobromide:

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

Eye disorders: Blurred vision, mydriasis.

Gastrointestinal disorders: dry mouth.

Immune System Disorders: Allergic reaction and anaphylactic reaction. Hypersensitivity reactions with respective laboratory and clinical manifestations, including asthma syndrome, mild to moderate reactions affecting skin, respiratory tract, and cardiovascular system, and symptoms such as rash, uticaria, oedema, pruritus, cardio-respiratory distress, have been reported.

Nervous system disorders: Drowsiness, dizziness, sedation and somnolence are commonly reported. Central nervous system stimulation including restlestness, hallucinations and confusion, has been less frequently reported following administration of hyoscine hydrobromide.

Caffeine:

High doses of caffeine may cause tremors and palpitations.

Section 4.9 has been changed completely and now reads:

4.9 Overdose

Paracetamol:

In case of overdose, contact a physician or poison control center immediately. Prompt medical attention is critical for adults as well as children even if no signs and/or symptoms are apparent.

Acute toxicity

The most important effect of acute intoxication is hepatotoxicity: hepatocellular damage is caused by the binding of reactive paracetamol metabolites to liver cell proteins. In therapeutic doses these metabolites are bound by glutathione, forming non-toxic conjugates. In the event of massive overdose the liver’s supply of SH-donors (which promote glutathione formation) is exhausted, toxic metabolites accumulate and liver cell necrosis occurs, with consequent impairment of liver function progressing to hepatic coma. Renal damage as a result of renal tubular necrosis has also been described independently.

The overdose threshold may be lowered in patients taking certain medicines or alcohol, or are seriously undernourished.

Chronic toxicity

Chronic toxicity includes diverse hepatic impairments (see Symptoms of intoxication). The data regarding the chronic toxicity and particularly the nephrotoxicity of paracetamol are controversial. Attention should be paid to the possible influence on peripheral blood cell count with chronic intake.

Symptoms of intoxication

The onset of acute intoxication is characterized by nausea, vomiting, abdominal pain, sweating and general malaise. The patient’s condition may improve for 24 to 48 hours, although the symptoms may not disappear completely.

The size of the liver increases rapidly, transaminases and bilirubin are elevated, prothrombin time becomes pathological, urinary output falls, slight azotemia may develop. Frequent clinical manifestations after 3 to 5 days are jaundice, fever, fetor hepaticus, haemorrhagic diathesis, hypoglycaemia, and liver failure. Hepatic failure may progress to all stages of hepatic encephalopathy, cerebral oedema, and death.

Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage.

Treatment of intoxication

Medical intensive care with close monitoring of vital signs, laboratory findings and circulatory status should generally be initiated.

Already if intoxication with Paracetamol is suspected an intravenous administration of SH-group donors (e.g. methionine, cysteamine or N-acetylcysteine) is useful within 10 hours of ingestion as they conjugate the reactive metabolites and thus aid their normal detoxification. N-acetylcysteine can be protective to a certain degree up to 48 hours after ingestion. Gastric lavage is useful within the first six hours. Haemodialysis and haemoperfusion support elimination of the substance. It is recommended to control the plasma concentration of paracetamol.

Codeine:

The toxic effects of codeine may be reversed by the administration of naloxone injection. 

Hyoscine hydrobromide:

The symptoms of overdosage are tachycardia, arrhythmia, blurring of vision, photophobia, and urinary retention.

Drowsiness is usual but paradoxical stimulation with hallucinations may occur. Treatment: gastric lavage or induced emesis and symptomatic treatment.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: 

Paracetamol: Other analgesics and antipyretics

Codeine: Opioids

Hyoscine hydrobromide:Antiemetics and antinauseants

Caffeine: Psychostimulants, agents used for ADHD and nootropics.

ATC-Codes:

Paracetamol: N02BE01

Codeine: N02AA08

Hyoscine hydrobromide: A04AD01

Caffeine: N06BC01

Paracetamol:  

Paracetamol, a para-aminophenol derivative, has analgesic and antipyretic properties and weak antiinflammatory activity.

The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and, to a lesser extent, through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitize pain receptors to mechanical or chemical stimulation.

Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulating center to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating, and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

Codeine Phosphate: Analgesic.

Hyoscine Hydrobromide:

Competitively inhibits muscarinic receptors for acetylcholine and acts as a nonselective muscarinic antagonist, producing both peripheral antimuscarinic properties and central sedative, antiemetic, and amnestic affects. This alkaloid is the most effective single agent to prevent motion sickness.

Caffeine:  CNS stimulant.