Mock Exam 1 of 0

The Lancashire Clinical Mock Exam 2023 Paper2

Tohidul March 13, 2023

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For each question, answer in the space provided.
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There are 120 questions in this paper. 30 extended matching questions and 90 single best answer questions.
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Extended Matching Questions (EMQs) 1-30

Question 47

Question 61

Epanutin Infatabs

Summary of Product Characteristics Updated 15-Jul-2022 | Upjohn UK Limited

1. Name of the medicinal product
2. Qualitative and quantitative composition
3. Pharmaceutical form
4. Clinical particulars
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Fertility, pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. Pharmacological properties
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. Pharmaceutical particulars
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text

1. Name of the medicinal product

EPANUTIN INFATABS 50 MG CHEWABLE TABLETS

2. Qualitative and quantitative composition

Each tablet contains phenytoin 50 mg.

Excipients with known effect

Each tablet also contains 474.80 mg confectioner’s sugar (sucrose ground together with maize starch to a fine powder), 0.0031 mg of the colouring agent E110 (Sunset yellow FCF) and 0.13 mg of sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Chewable tablet.

A yellow triangular chewable tablet with flat sides, a bevelled edge and a breaking line on one side with P-D 007 imprinted on the other side.

4. Clinical particulars

4.1 Therapeutic indications

Control of tonic-clonic seizures (grand mal epilepsy), partial seizures (focal including temporal lobe) or a combination of these, and for the prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury. Epanutin has also been employed in the treatment of trigeminal neuralgia but it should only be used as second line therapy if carbamazepine is ineffective or patients are intolerant to carbamazepine.

4.2 Posology and method of administration

Dosage:

Dosage should be individualised as there may be wide interpatient variability in phenytoin serum levels with equivalent dosage. Epanutin should be introduced in small dosages with gradual increments until control is achieved or until toxic effects appear. In some cases serum level determinations may be necessary for optimal dosage adjustments – the clinically effective level is usually 10 mcg/mL- 20 mcg/mL (40-80 micromoles/l) although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin. With recommended dosage a period of 7 to 10 days may be required to achieve steady state serum levels with Epanutin and changes in dosage should not be carried out at intervals shorter than 7 to 10 days. Maintenance of treatment should be the lowest dose of anticonvulsant consistent with control of seizures.

Epanutin Capsules, Suspension and Infatabs:

Epanutin Capsules contain phenytoin sodium whereas Epanutin Suspension and Epanutin Infatabs contain phenytoin. Although 100 mg of phenytoin sodium is equivalent to 92 mg of phenytoin on a molecular weight basis, these molecular equivalents are not necessarily biologically equivalent. Physicians should therefore exercise care in those situations where it is necessary to change the dosage form and serum level monitoring is advised.

Posology

Adult Dosage for Seizures:

Initially 3 to 4 mg/kg/day with subsequent dosage adjustment if necessary. For most adults a satisfactory maintenance dose will be 200 mg to 500 mg daily in single or divided doses. Exceptionally, a daily dose outside this range may be indicated. Dosage should normally be adjusted according to serum levels where assay facilities exist.

Dosing in Special Populations

Patients with Renal or Hepatic Disease:

See section 4.4.

Adult Dosage for Trigeminal Neuralgia:

The clinically effective dose has not been established in clinical trials. In adults, 300-500 mg daily given in divided doses has been reported in the literature. Dosing should be adjusted based on clinical response. Determination of serum phenytoin levels is advised. Levels of total phenytoin should not exceed 20 mcg/ml.

Elderly (over 65 years):

Phenytoin clearance may be decreased in elderly patients and lower or less frequent dosing may be required (see section 5.2 Special Populations – Age). As with adults the dosage of Epanutin should be titrated to the patient’s individual requirements using the same guidelines. As older people tend to receive multiple drug therapies, the possibility of drug interactions should be borne in mind.

Paediatric population Dosage for Seizures:

Initially, 5 mg/kg/day in two divided doses, with subsequent dosage individualised to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 mg/kg -8 mg/kg.

Method of administration

For oral administration only.

The chewable tablet is not intended to dissolve without mastication and therefore it must be chewed before swallowing.

Neonates:

The absorption of phenytoin following oral administration in neonates is unpredictable. Furthermore, the metabolism of phenytoin may be depressed. It is therefore especially important to monitor serum levels in the neonate.

4.3 Contraindications

Phenytoin is contraindicated in those patients who are hypersensitive to phenytoin, or to any of the excipients listed in section 6.1, or other hydantoins.

Co-administration of phenytoin is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

4.4 Special warnings and precautions for use

General

Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence seizures are present together, combined drug therapy is needed.

Phenytoin is not indicated for seizures due to hypoglycaemia or other metabolic causes.

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgement of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anti-epileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anti-epileptic drug not belonging to the hydantoin chemical class.

Phenytoin may precipitate or aggravate absence seizures and myoclonic seizures.

Acute alcohol intake may increase phenytoin serum levels while chronic alcoholism may decrease serum levels.

Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total plasma phenytoin concentrations should be made with caution. Unbound concentration of phenytoin may be elevated in patients with hyperbilirubinemia. Unbound phenytoin concentrations may be more useful in these patient populations.

Herbal preparations containing St. John’s wort (Hypericum perforatum) should not be used while taking phenytoin due to the risk of decreased plasma concentrations and reduced clinical effects of phenytoin (see section 4.5).

Suicide

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for phenytoin.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Cardiac Effects

Cases of bradycardia and asystole/cardiac arrest have been reported, most commonly in association with phenytoin toxicity (see section 4.9), but also at recommended phenytoin doses and levels.

Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (HSS/DRESS)

Hypersensitivity Syndrome (HSS) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking anticonvulsant drugs, including phenytoin. Some of these events have been fatal or life threatening.

HSS/DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, haematological abnormalities, myocarditis, myositis or pneumonitis. Initial symptoms may resemble an acute viral infection. Other common manifestations include arthralgias, jaundice, hepatomegaly, leucocytosis, and eosinophilia. The interval between the first drug exposure and symptoms is usually 2 to 4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months. If such signs and symptoms occur, the patient should be evaluated immediately. Phenytoin should be discontinued if an alternative aetiology for the signs and symptoms cannot be established.

Patients at higher risk for developing HSS/DRESS include black patients, patients who have experienced this syndrome in the past (with phenytoin or other anticonvulsant drugs), patients who have a family history of this syndrome and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals.

Serious Cutaneous Adverse Reactions

Epanutin can cause severe cutaneous adverse reactions (SCARs) such as acute gerneralized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and DRESS, which can be fatal (see section 4.8 Skin and subcutaneous tissue disorders). Although serious skin reactions may occur without warning, patients should be advised of the signs and symptoms of HSS/DRESS (see section 4.4 Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (HSS/DRESS)), occurrence of rash and should be monitored closely for skin reactions. Patients should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Epanutin treatment should be discontinued. The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis. If the patient has developed SJS or TEN with the use of Epanutin, Epanutin must not be re-started in this patient at any time.

If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated. The risk of serious skin reactions and other hypersensitivity reactions to phenytoin may be higher in black patients.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of human leukocyte antigen HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including phenytoin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available.

HLA-B*1502 may be associated with an increased risk of developing SJS in individuals of Thai and Han Chinese Origin when treated with phenytoin. If these patients are known to be positive for HLA-B*1502, the use of phenytoin should only be considered if the benefits are thought to exceed risks.

In the Caucasian and Japanese population, the frequency of HLA-B*1502 allele is extremely low, and thus it is not possible at present to conclude on risk association. Adequate information about risk association in other ethnicities is currently not available.

Case-control, genome-wide association studies in Taiwanese, Japanese, Malaysian and Thai patients have identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant.

CYP2C9 metabolism

Phenytoin is metabolised by the CYP450 CYP2C9 enzyme. Patients who are carriers of the decreased function CYP2C9*2 or CYP2C9*3 variants (intermediate or poor metabolisers of CYP2C9 substrates) may be at risk of increased phenytoin plasma concentrations and subsequent toxicity. In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles, close monitoring of clinical response is advised and monitoring of plasma phenytoin concentrations may be required.

Angioedema

Angioedema has been reported in patients treated with phenytoin and fosphenytoin. Phenytoin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur (see section 4.8 Immune system disorders).

Hepatic Injury

Phenytoin is highly protein bound and extensively metabolised by the liver. Reduced dosage to prevent accumulation and toxicity may therefore be required in patients with impaired liver function. Where protein binding is reduced, as in uraemia, total serum phenytoin levels will be reduced accordingly. However, the pharmacologically active free drug concentration is unlikely to be altered. Therefore, under these circumstances therapeutic control may be achieved with total phenytoin levels below the normal range of 10 mcg/mL – 20 mcg/mL (40-80 micromoles/l).

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These incidents usually occur within the first 2 months of treatment and may be associated with HSS/DRESS (see section 4.4 Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (HSS/DRESS)). Patients with impaired liver function, older patients or those who are gravely ill may show early signs of toxicity.

The risk of hepatotoxicity and other hypersensitivity reactions to phenytoin may be higher in black patients.

Haematopoietic System

Haematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local and generalised) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s Disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without signs and symptoms resembling HSS/DRESS (see section 4.4). In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Central Nervous System Effect

Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as “delirium”, “psychosis”, or “encephalopathy”, or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum drug level determinations are recommended. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination of therapy with phenytoin is recommended.

Musculoskeletal Effect

Phenytoin and other anticonvulsants that have been shown to induce the CYP450 enzyme are thought to affect bone mineral metabolism indirectly by increasing the metabolism of vitamin D₃. This may lead to vitamin D deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically treated epileptic patients.

Metabolic Effect

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using the medication in patients suffering from this disease.

Phenytoin may affect glucose metabolism and inhibit insulin release. Hyperglycaemia has been reported in association with toxic levels.

Women of Childbearing Potential

Phenytoin may cause foetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes (see section 4.6).

Epanutin should not be used in women of childbearing potential unless the benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options.

Before the initiation of treatment with phenytoin in a woman of childbearing potential, pregnancy testing should be considered.

Women of childbearing potential should be fully informed of the potential risk to the foetus if they take phenytoin during pregnancy.

Women of childbearing potential should be counselled regarding the need to consult their physician as soon as they are is planning pregnancy to discuss switching to alternative treatments prior to conception and before contraception is discontinued (see section 4.6).

Women of childbearing potential should be counselled to contact their doctor immediately if they becomes pregnant or might be pregnant and are taking phenytoin.

Information on Excipients

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine as it contains sucrose.

This product contains confectioner’s sugar (sucrose ground together with maize starch to a fine powder) and may be harmful to the teeth when used over an extended period.

Epanutin Infatabs contain the excipient Sunset yellow FCF (E110) which may cause allergic reactions.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Drug Interactions

Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome (CYP) P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes and may reduce the levels of drugs metabolized by these enzymes.

There are many drugs that may increase or decrease serum phenytoin levels or that phenytoin may affect. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected.

Drugs that may increase phenytoin serum levels

Table 1 summarizes the drug classes that may potentially increase phenytoin serum levels.

Table 1 Drugs that may potentially increase phenytoin serum levels

Drug Classes	*Drugs in each Class (such as)**
Alcohol (acute intake)
Analgesic/Anti-inflammatory agents	azapropazone phenylbutazone salicylates
Anesthetics	halothane
Antibacterial agents	chloramphenicol erythromycin isoniazid sulfadiazine sulfamethizole sulfamethoxazole- trimethoprim sulfaphenazole sulfisoxazole sulfonamides
Anticonvulsants	felbamate oxcarbazepine sodium valproate succinimides topiramate
Antifungal agents	amphotericin B fluconazole itraconazole ketoconazole miconazole voriconazole
Antineoplastic agents	capecitabine fluorouracil
Benzodiazepines/Psychotropic agents	chlordiazepoxide diazepam disulfiram methylphenidate trazodone viloxazine
Calcium channel blockers/Cardiovascular agents	amiodarone dicoumarol diltiazem nifedipine ticlopidine
H2-antagonists	cimetidine
HMG-CoA reductase inhibitors	fluvastatin
Hormones	oestrogens
Immunosuppressant drugs	tacrolimus
Oral hypoglycemic agents	tolbutamide
Proton pump inhibitors	omeprazole
Serotonin re-uptake inhibitors	fluoxetine fluvoxamine sertraline

* This list is not intended to be inclusive or comprehensive. Individual product information should be consulted.

Drugs that may decrease phenytoin serum levels

Table 2 summarizes the drug classes that may potentially decrease phenytoin plasma levels.

Table 2 Drugs that may decrease phenytoin plasma levels

Drug Classes	*Drugs in each Class (such as)**
Alcohol (chronic intake)
Antibacterial agents	ciprofloxacinrifampicin
Anticonvulsants	vigabatrin
Antineoplastic agents	bleomycin carboplatin cisplatin doxorubicin methotrexate
Antiulcer agents	sucralfate
Antiretrovirals	fosamprenavir nelfinavir ritonavir
Bronchodilators	theophylline
Cardiovascular agents	reserpine
Folic acid	folic acid
Hyperglycemic agents	diazoxide
St. John’s Wort	St. John’s wort

* This list is not intended to be inclusive or comprehensive. Individual product information should be consulted.

Serum levels of phenytoin can be reduced by concomitant use of the herbal preparations containing St. John’s wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes by St. John’s wort. Herbal preparations containing St. John’s wort should therefore not be combined with phenytoin. The inducing effect may persist for at least 2 weeks after cessation of treatment with St, John’s wort. If a patient is already taking St. John’s wort check the anticonvulsant levels and stop St. John’s wort. Anticonvulsant levels may increase on stopping St. John’s wort. The dose of anticonvulsant may need adjusting.

Drugs that may either increase or decrease phenytoin serum levels

Table 3 summarizes the drug classes that may either increase or decrease phenytoin serum levels.

Table 3 Drugs that may either increase or decrease phenytoin serum levels

Drug Classes	*Drugs in each Class (such as)**
Antibacterial agents	ciprofloxacin
Anticonvulsants	carbamazepine phenobarbital sodium valproate valproic acid
Antineoplastic agents
Psychotropic agents	chlordiazepoxide diazepam phenothiazines

* This list is not intended to be inclusive or comprehensive. Individual product information should be consulted.

Drugs whose serum levels and/or effects may be altered by phenytoin

Table 4 summarizes the drug classes whose serum levels and/or effects may be altered by phenytoin.

Table 4 Drugs whose serum levels and/or effects may be altered by phenytoin

Drug Classes	*Drugs in each Class (such as)**
Antibacterial agents	doxycycline rifampicin tetracycline
Anticoagulants	apixaban dabigatran edoxaban rivaroxaban warfarin
Anticonvulsants	carbamazepine lacosamide lamotrigine phenobarbital sodium valproate valproic acid
Antifungal agents	azoles posaconazole voriconazole
Antihelminthics	albendazole praziquantel
Antineoplastic agents	teniposide
Antiplatelets	ticagrelor
Antiretrovirals	delavirdine efavirenz fosamprenavir indinavir lopinavir/ritonavir nelfinavir ritonavir saquinavir
Bronchodilators	theophylline
Calcium channel blockers/Cardiovascular agents	digitoxin digoxin disopyramide mexiletine nicardipine nimodipine nisoldipine quinidine verapamil
Corticosteroids
Cyclosporine
Diuretics	furosemide
HMG-CoA reductase inhibitors	atorvastatin fluvastatin simvastatin
Hormones	oestrogens oral contraceptives
Hyperglycemic agents	diazoxide
Immunosuppressant drugs
Neuromuscular blocking agents	alcuronium cisatracurium pancuronium rocuronium vecuronium
Opioid analgesics	methadone
Oral hypoglycemic agents	chlorpropamide glyburide tolbutamide
Psychotropic agents/Antidepressants	clozapine paroxetine quetiapine sertraline
Vitamin D	vitamin D

* This list is not intended to be inclusive or comprehensive. Individual product information should be consulted.

Although not a true pharmacokinetic interaction, tricyclic antidepressants and phenothiazines may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.

Hyperammonaemia with Concomitant Use of Valproate

Concomitant administration of phenytoin and valproate has been associated with an increased risk of valproate-associated hyperammonaemia. Patients treated concomitantly with these two drugs should be monitored for signs and symptoms of hyperammonaemia.

Drug-Laboratory Test InteractionsPhenytoin may cause a slight decrease in serum levels of total and free thyroxine, possibly as a result of enhanced peripheral metabolism. These changes do not lead to clinical hypothyroidism and do not affect the levels of circulating TSH. The latter can therefore be used for diagnosing hypothyroidism in the patient on phenytoin. Phenytoin does not interfere with uptake and suppression tests used in the diagnosis of hypothyroidism. It may, however, produce lower than normal values for dexamethasone or metapyrone tests. Phenytoin may cause raised serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase and lowered serum levels of calcium and folic acid. It is recommended that serum folate

concentrations be measured at least once every 6 months, and folic acid supplements given if necessary. Phenytoin may affect blood sugar metabolism tests.

4.6 Fertility, pregnancy and lactation

Pregnancy

Risk related to antiepileptic medicinal products in general

When possible, medical advice regarding the potential risks to a foetus caused by both seizures and antiepileptic treatment should be given to all women of childbearing potential taking antiepileptic treatment, and especially to women planning pregnancy and women who are pregnant. Antiepileptic treatment should be reviewed regularly and especially when a woman is planning to become pregnant. In pregnant women being treated for epilepsy, sudden discontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. As a general principle, monotherapy is preferred for treating epilepsy in pregnancy whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated AEDs.

Risk related to phenytoin

Phenytoin crosses the placenta in humans. Similar concentrations of phenytoin have been reported in the umbilical cord and maternal blood.

Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Studies have shown that phenytoin exposure during pregnancy is associated with an approximate 6% frequency of major malformations, which is hiher than the frequency in the general population of 2-3%. Malformations such as orofacial clefts, cardiac defects, craniofacial defects, nail and digit hypoplasia, and growth abnormalities (including microcephaly and prenatal growth deficiency) have been reported either individually or as part of a Fetal Hydantoin Syndrome among children born to women with epilepsy who used phenytoin during pregnancy.

Neurodevelopmental disorders have been reported among children born to women with epilepsy who used phenytoin alone or in combination with other AEDs during pregnancy. A small number of studies have found an increase of serious adverse outcomes compared to control subjects including fetal hydantoin syndrome and below average IQ. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. However, the respective role of antiepileptic drugs and other factors in the increased risk is not determined.

Epanutin should not be used during pregnancy and in women of childbearing potential unless the benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options. The woman should be fully informed of and understand the risks of taking phenytoin during pregnancy.

If based on a careful evaluation of the risks and the benefits, no alternative treatment option is suitable, and treatment with Epanutin is continued, the lowest effective dose of phenytoin should be used. If a woman is planning to become pregnant, all efforts should be made to switch to appropriate alternative treatment prior to conception and before contraception is discontinued. If a woman becomes pregnant while taking phenytoin, she should be referred to a specialist to reassess phenytoin treatment and consider alternative treatment options.An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin

concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see section 4.2). However, postpartum restoration of the original dosage will probably be indicated.

Reproductive and developmental toxicity has been observed in animals (see section 5.3).

Phenytoin is teratogenic in rats, mice and rabbits.

Women of childbearing potential

Epanutin should not be used in women of childbearing potential unless the potential benefit is judged to outweigh the risks following careful consideration of alternative suitable treatment options. The woman should be fully informed of and understand the risk of potential harm to the foetus if phenytoin is taken during pregnancy and therefore the importance of planning any pregnancy. Pregnancy testing in women of childbearing potential should be considered prior to initiating treatment with Epanutin.

Women of childbearing potential should use effective contraception during treatment and for one month after stopping treatment. Due to enzyme induction, Epanutin may result in a failure of the therapeutic effect of hormonal contraceptives, therefore, women of childbearing potential should be counselled regarding the use of other effective contraceptive methods (see section 4.5). At least one effective method of contraception (such as an intra-uterine device) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, involving the patient in the discussion, when choosing the contraception method.

Women planning to become pregnant and in pregnant women

In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible. Epanutin should not be discontinued prior to reassessment of the treatment. When possible, patients should be informed of the potential harm to the foetus. If based on a careful evaluation of the risks and the benefits, Epanutin treatment is continued during the pregnancy, it is recommended to use the lowest effective dose and to institute specialized prenatal monitoring, oriented on the possible occurrence of the described malformations.

In neonates

Haemorrhagic syndrome has been reported in neonates born from epileptic mothers receiving phenytoin. Vitamin K has been shown to prevent or correct this defect and has been recommended to be given to the mother during the last gestational month and to the neonate after birth.

Post-natal monitoring/children

In case of exposure during pregnancy, children should be closely monitored in relation to neurodevelopmental disorders in order to provide specialized care as soon as possible, if necessary.

Breast-feeding

Following administration of oral phenytoin, phenytoin appears to be excreted in low concentrations in human milk. Therefore, breast feeding is not recommended for women receiving Epanutin.

Fertility

MedDRA System organ class	Frequency	Undesirable Effects
*Blood and lymphatic system disorders*	Not Known	Haematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression, and aplastic anaemia. While macrocytosis and megaloblastic anaemia have occurred, these conditions usually respond to folic acid therapy.There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local and generalised) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease (see section 4.4).Frequent blood counts should be carried out during treatment with phenytoin.Pure red cell aplasia has also been reported.
*Immune system disorders*	Not Known	Anaphylactoid reaction, anaphylactic reaction, immunoglobulin abnormalities may occur, angioedema (see section 4.4).
*Metabolism and nutrition disorders*	Not Known	Hypocalcaemia, hypophosphataemia in chronically treated epileptic patients.
*Psychiatric disorders*	Not Known	Insomnia, transient nervousness.
*Nervous system disorders*	Not Known	Adverse reactions in this body system are common and are usually dose-related. Reactions include nystagmus, ataxia, dysarthria, decreased coordination and mental confusion. Cerebellar atrophy has been reported, and appears more likely in settings of elevated phenytoin levels and/or long-term phenytoin use (see section 4.4). Dizziness, motor twitchings, headache, paraesthesia, somnolence and dysgeusia have also been observed.There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. There are occasional reports of irreversible cerebellar dysfunction associated with severe phenytoin overdosage.A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

*Ear and labyrinth disorders*	Not Known	Vertigo
*Vascular disorders*	Not Known	Polyarteritis nodosa may occur.
*Respiratory, thoracic and mediastinal disorders*	Not Known	Pneumonitis.
*Gastrointestinal disorders*	Not Known	Vomiting, nausea, gingival hyperplasia constipation (see section 4.4).
*Hepatobiliary disorders*	Not Known	Acute hepatic failure, hepatitis toxic, liver injury.
*Skin and subcutaneous tissue disorders*	Not Known	Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash is the most common; dermatitis is seen more rarely. Other more serious and rare forms have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, hirsutism, hypertrichosis, Peyronie’s Disease and Dupuytren’s contracture may occur rarely, coarsening of the facial features, enlargement of the lips, Severe cutaneous adverse reactions (SCARs): acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported very rarely (see section 4.4). Drug reaction with eosinophilia and systemic symptoms (DRESS) (see section 4.4) has been reported and may in rare cases be fatal (the syndrome may include, but is not limited to, symptoms such as arthralgia, eosinophilia, pyrexia, hepatic function abnormal, lymphadenopathy or rash). Several individual case reports have suggested that there may be an increased, although still rare, incidence of hypersensitivity reactions, including skin rash and hepatotoxicity, in black patients. Urticaria has been reported.
*Musculoskeletal and connective tissue disorders*	Not Known	Systemic lupus erythematosus, arthropathy. There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with phenytoin. The mechanism by which phenytoin affects bone metabolism has not been identified. However, phenytoin has been shown to induce the CYP450 enzyme, which can affect bone mineral metabolism indirectly by increasing the metabolism of Vitamin D3. This may lead to vitamin D deficiency and heightened risk of osteomalacia, osteoporosis.
*Renal and urinary disorders*	Not Known	Tubulointerstitial nephritis.
*Injury, poisoning and procedural complications*	Not Known	Fractures.
*Investigations*	Not Known	Thyroid function test abnormal.

In animal studies, phenytoin had no direct effect on fertility.

4.7 Effects on ability to drive and use machines

Caution is recommended in patients performing skilled tasks (e.g. driving or operating machines) as treatment with phenytoin may cause central nervous system adverse effects such as dizziness and drowsiness (see section 4.8).

4.8 Undesirable effects

In the table below all adverse reactions with phenytoin are listed by class and frequency Not Known (cannot be estimated from available data).

Paediatric population

The adverse event profile of phenytoin is generally similar between children and adults. Gingival hyperplasia occurs more frequently in paediatric patients and in patients with poor oral hygiene.

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

The lethal dose in children is not known. The mean lethal dose for adults is estimated to be 2 g to 5 g. The initial symptoms are nystagmus, ataxia and dysarthria. The patient then becomes comatose, the pupils are unresponsive and hypotension occurs followed by respiratory depression and apnoea. Bradycardia and asystole/cardiac arrest have been reported (see section 4.4). Death is due to respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus on lateral gaze usually appears at 20 mg/l, and ataxia at 30 mg/l, dysarthria and lethargy appear when the serum concentration is greater than 40 mg/l, but a concentration as high as 50 mg/l has been reported without evidence of toxicity.

As much as 25 times therapeutic dose has been taken to result in serum concentration over 100 mg/l (400 micromoles/l) with complete recovery. Irreversible cerebellar dysfunction and atrophy have been reported.

Treatment:

Treatment is non-specific since there is no known antidote. If ingested within the previous 4 hours the stomach should be emptied. If the gag reflex is absent, the airway should be supported. Oxygen, and assisted ventilation may be necessary for central nervous system, respiratory and cardiovascular depression. Haemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been utilised in the treat-ment of severe intoxication in children.

In acute overdosage the possibility of the presence of other CNS depressants, including alcohol, should be borne in mind.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, ATC Code: N03AB02.

Phenytoin is effective in various animal models of generalised convulsive disorders, reasonably effective in models of partial seizures but relatively ineffective in models of myoclonic seizures.

It appears to stabilise rather than raise the seizure threshold and prevents spread of seizure activity rather than abolish the primary focus of seizure discharge.

The mechanism by which phenytoin exerts its anticonvulsant action has not been fully elucidated however, possible contributory effects include:

1. Non-synaptic effects to reduce sodium conductance, enhance active sodium extrusion, block repetitive firing and reduce post-tetanic potentiation.

2. Post-synaptic action to enhance GABA-mediated inhibition and reduce excitatory synaptic transmission.

3. Pre-synaptic actions to reduce calcium entry and block release of neurotransmitter.

5.2 Pharmacokinetic properties

Absorption

Phenytoin is absorbed from the small intestine after oral administration. Various formulation factors may affect the bioavailability of phenytoin, however, non-linear techniques have estimated absorption to be essentially complete. After absorption it is distributed into body fluid including the cerebrospinal fluid (CSF). Its volume of distribution has been estimated to be between 0.52 and 1.19 litres/kg, and it is highly protein bound (usually 90% in adults).

Distribution

The plasma half-life of phenytoin in man averages 22 hours with a range of 7 to 42 hours. Steady state therapeutic drug levels are achieved at least 7 to 10 days after initiation of therapy.

Biotransformation

Phenytoin is hydroxylated in the liver by an enzyme system which is saturable. Small incremental doses may produce very substantial increases in serum levels when these are in the upper range of therapeutic concentrations.

Elimination

The parameters controlling elimination are also subject to wide interpatient variation. The serum level achieved by a given dose is therefore also subject to wide variation.

Special Populations

Patients with Renal or Hepatic Disease: see section 4.4.

Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see section 4.2 Dosing in Special Populations – Elderly (over 65 years)).

5.3 Preclinical safety data

Phenytoin causes embryofoetal death and growth retardation in rats, mice, and rabbits. Phenytoin is teratogenic in rats (craniofacial defects including cleft palate, cardiovascular malformations, neural and renal defects, and limb abnormalities), mice (cleft lip, cleft palate, neural and renal defects, limb abnormalities, and digital and ocular abnormalities) and rabbits (cleft palate, limb abnormalities, and digital and ocular abnormalities). The defects produced are similar to major malformations observed in humans and abnormalities described for foetal hydantoin syndrome. The teratogenic effects of phenytoin in animals occur at therapeutic exposures, and therefore a risk to the patients cannot be ruled out.

Carcinogenesis

Two-year carcinogenicity studies in mice and rats showed an increased number of hepatocellular adenomas in mice, but not rats, at plasma concentrations relevant for humans. The clinical significance of these rodent tumours is unknown.

Genetic toxicity studies showed that phenytoin was not mutagenic in bacteria or in mammalian cells in vitro. It is clastogenic in vitro but not in vivo.

6. Pharmaceutical particulars

6.1 List of excipients

Confectioner’s sugar

Saccharin sodium

Spearmint flavour

Magnesium stearate

Purified talc

E104 (quinoline yellow)

E110 (sunset yellow FCF)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

White HDPE squeeze and turn bottles with child-resistant squeeze and turn polypropylene closures, containing 200 tablets.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Upjohn UK Limited

Sandwich

Kent

CT13 9NJ

United Kingdom.

8. Marketing authorisation number(s)

PL 50622/0024.

9. Date of first authorisation/renewal of the authorisation

Date of latest renewal: 01 September 2003.

10. Date of revision of the text

07/2022

Ref: EP 45_2

Company Contact Details

Upjohn UK Limited

Address

Building 4, Trident Place, Mosquito Way, Hatfield , Hertfordshire, AL10 9UL, UK

Telephone

+44 (0)1707 853 000

Medical Information Direct Line

+44 (0)1707 853 000

Customer Care direct line

+44 (0)1707 853 000 select option 2

Stock Availability

+44 (0)1707 853 000 select option 2

Questions 65

Questions 67

Ciprofloxacin

Navigate to section

Indications and dose
Unlicensed use
Important safety information
Contra-indications
Cautions
Interactions
Side-effects
Allergy and cross-sensitivity
Pregnancy
Breast feeding
Renal impairment
Prescribing and dispensing information
Handling and storage
Patient and carer advice
National funding/access decisions
Medicinal forms
Related treatment summaries
Other drugs in class

Interactions

View interactions for ciprofloxacin

Medicinal forms and pricing

There can be variation in the licensing of different medicines containing the same drug.

Forms available from special-order manufacturers include: oral suspension, ear drops, eye drops, eye ointment.

View all medicinal forms and pricing information

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Tablet
Oral suspension
Infusion
Solution for infusion
Ear drops
Eye drops

Indications and dose

For ciprofloxacin

Superficial bacterial eye infectionfor ciprofloxacin

To the eye using eye drop

Child

Apply 4 times a day for maximum duration of treatment 21 days.

Adult

Apply 4 times a day for maximum duration of treatment 21 days.

To the eye using eye ointment

Child 1–17 years

Apply 1.25 centimetres 3 times a day for 2 days, then apply 1.25 centimetres twice daily for 5 days.

Adult

Apply 1.25 centimetres 3 times a day for 2 days, then apply 1.25 centimetres twice daily for 5 days.

Superficial bacterial eye infection (severe infection)for ciprofloxacin

To the eye using eye drop

Child

Apply every 2 hours during waking hours for 2 days, then apply 4 times a day for maximum duration of treatment 21 days.

Adult

Apply every 2 hours during waking hours for 2 days, then apply 4 times a day for maximum duration of treatment 21 days.

Corneal ulcerfor ciprofloxacin

To the eye using eye drop

Child

Apply every 15 minutes for 6 hours, then apply every 30 minutes for the remainder of day 1, then apply every 1 hour on day 2, then apply every 4 hours on days 3–14, maximum duration of treatment 21 days, to be administered throughout the day and night.

Adult

To the eye using eye ointment

Child 1–17 years

Apply 1.25 centimetres every 1–2 hours for 2 days, then apply 1.25 centimetres every 4 hours for the next 12 days, to be administered throughout the day and night.

Adult

Apply 1.25 centimetres every 1–2 hours for 2 days, then apply 1.25 centimetres every 4 hours for the next 12 days, to be administered throughout the day and night.

Acute otitis externa for ciprofloxacin

To the ear

Child 1–17 years

Apply 0.25 mL twice daily for 7 days, each 0.25 mL dose contains 0.5 mg ciprofloxacin.

Adult

Apply 0.25 mL twice daily for 7 days, each 0.25 mL dose contains 0.5 mg ciprofloxacin.

Moderate diabetic foot infection, Severe diabetic foot infectionfor ciprofloxacin

By mouth

Adult

500 mg twice daily.

By intravenous infusion

Adult

400 mg every 8–12 hours, to be given over 60 minutes.

Fistulating Crohn’s diseasefor ciprofloxacin

By mouth

Adult

500 mg twice daily.

Acute diverticulitis [in combination with metronidazole] (administered on expert advice)for ciprofloxacin

By mouth

Adult

500 mg twice daily for 5 days then review.

By intravenous infusion

Adult

400 mg every 8–12 hours, to be given over 60 minutes.

Respiratory-tract infectionsfor ciprofloxacin

By mouth

Adult

500–750 mg twice daily.

By intravenous infusion

Adult

400 mg every 8–12 hours, to be given over 60 minutes.

Pseudomonal lower respiratory-tract infection in cystic fibrosisfor ciprofloxacin

By mouth

Adult

750 mg twice daily.

Urinary-tract infectionsfor ciprofloxacin

By mouth

Adult

250–750 mg twice daily.

By intravenous infusion

Adult

400 mg every 8–12 hours, to be given over 60 minutes.

Acute prostatitisfor ciprofloxacin

By mouth

Adult

500 mg twice daily for 14 days then carry out a clinical assessment to decide whether to continue for a further 14 days.

By intravenous infusion

Adult

400 mg every 8–12 hours.

Uncomplicated gonorrhoea [anogenital and pharyngeal infection, when sensitivity confirmed]for ciprofloxacin

By mouth

Adult

500 mg for 1 dose.

Disseminated gonococcal infection [when sensitivity confirmed]for ciprofloxacin

By intravenous infusion

Adult

500 mg every 12 hours for 7 days, may be switched 24–48 hours after symptoms improve to a suitable oral antibacterial.

By mouth

Adult

500 mg twice daily, following intravenous antibacterial treatment, starting 24–48 hours after symptoms improve, to give 7 days treatment in total.

Most other infectionsfor ciprofloxacin

By mouth

Adult

Initially 500 mg twice daily; increased to 750 mg twice daily, in severe or deep-seated infection.

By intravenous infusion

Adult

400 mg every 8–12 hours, to be given over 60 minutes.

Surgical prophylaxisfor ciprofloxacin

By mouth

Adult

750 mg, to be taken 60 minutes before procedure.

Anthrax (treatment and post-exposure prophylaxis)for ciprofloxacin

By mouth

Adult

500 mg twice daily.

By intravenous infusion

Adult

400 mg every 12 hours, to be given over 60 minutes.

Prevention of secondary case of meningococcal meningitisfor ciprofloxacin

By mouth

Child 1 month–4 years

30 mg/kg (max. per dose 125 mg) for 1 dose.

Child 5–11 years

250 mg for 1 dose.

Child 12–17 years

500 mg for 1 dose.

Adult

500 mg for 1 dose.

Acute pyelonephritis, Urinary tract infection (catheter-associated)for ciprofloxacin

By mouth

Adult

500 mg twice daily for 7 days.

By intravenous infusion

Adult

400 mg every 8–12 hours.

Unlicensed use

Unlicensed use For ciprofloxacin

With intravenous use or oral use:

Ciprofloxacin is used for the treatment of disseminated gonococcal infection, but is not licensed for this indication.

With oral use in children:

Ciprofloxacin is used for the treatment of uncomplicated gonorrhoea, but is not licensed for this indication.

When used by eye in children:

Eye ointment not licensed for use in children under 1 year.

With intravenous use or oral use in children:

Not licensed for use in children under 1 year of age.

Licensed for use in children over 1 year for complicated urinary-tract infections, for pseudomonal lower respiratory-tract infections in cystic fibrosis, for prophylaxis and treatment of inhalational anthrax. Licensed for use in children over 1 year for other infections where the benefit is considered to outweigh the potential risks.

Not licensed for use in children for gastro-intestinal anthrax.

Not licensed for use in children for prophylaxis of meningococcal meningitis.

Important safety information

Important safety information For all quinolones

With intravenous use or oral use or when used by inhalation:

The CSM has warned that quinolones may induce convulsions in patients with or without a history of convulsions; taking NSAIDs at the same time may also induce them.

Tendon damage

With intravenous use or oral use or when used by inhalation in adults:

Tendon damage (including rupture) has been reported rarely in patients receiving quinolones. Tendon rupture may occur within 48 hours of starting treatment; cases have also been reported several months after stopping a quinolone. Healthcare professionals are reminded that:

quinolones are contra-indicated in patients with a history of tendon disorders related to quinolone use;
patients over 60 years of age are more prone to tendon damage;
the risk of tendon damage is increased by the concomitant use of corticosteroids;
if tendinitis is suspected, the quinolone should be discontinued immediately.

Tendon damage

With intravenous use or oral use in children:

quinolones are contra-indicated in patients with a history of tendon disorders related to quinolone use;
the risk of tendon damage is increased by the concomitant use of corticosteroids;
if tendinitis is suspected, the quinolone should be discontinued immediately.

MHRA/CHM advice: Systemic and inhaled fluoroquinolones: small increased risk of aortic aneurysm and dissection; advice for prescribing in high-risk patients (November 2018)

With intravenous use or oral use or when used by inhalation in adults:

The MHRA advises that benefit-risk should be assessed and other therapeutic options considered before using fluoroquinolones in patients at risk of aortic aneurysm and dissection.

Patients (particularly the elderly and those at risk) and their carers should be informed about rare events of aortic aneurysm and dissection, and advised to seek immediate medical attention if sudden-onset severe abdominal, chest, or back pain develops.

MHRA/CHM advice: Systemic and inhaled fluoroquinolones: small increased risk of aortic aneurysm and dissection; advice for prescribing in high-risk patients (November 2018)

With intravenous use or oral use in children:

The MHRA advises that benefit-risk should be assessed and other therapeutic options considered before using fluoroquinolones in patients at risk of aortic aneurysm and dissection.

Patients (particularly those at risk) and their carers should be informed about rare events of aortic aneurysm and dissection, and advised to seek immediate medical attention if sudden-onset severe abdominal, chest, or back pain develops.

MHRA/CHM advice: Fluoroquinolone antibiotics: new restrictions and precautions for use due to very rare reports of disabling and potentially long-lasting or irreversible side effects (March 2019)

With intravenous use or oral use or when used by inhalation in adults:

Disabling, long-lasting or potentially irreversible adverse reactions affecting musculoskeletal and nervous systems have been reported very rarely with fluoroquinolone antibiotics. Healthcare professionals are advised to inform patients to stop treatment at the first signs of a serious adverse reaction, such as tendinitis or tendon rupture, muscle pain, muscle weakness, joint pain, joint swelling, peripheral neuropathy, and CNS effects, and to contact their doctor immediately.

Fluoroquinolones should not be prescribed for non-severe or self-limiting infections, or non-bacterial conditions. Unless other commonly recommended antibiotics are inappropriate, fluoroquinolones should not be prescribed for some mild to moderate infections, such as acute exacerbation of chronic bronchitis and chronic obstructive pulmonary disease, and ciprofloxacin or levofloxacin should not be prescribed for uncomplicated cystitis.

Fluoroquinolones should be avoided in patients who have previously had serious adverse reactions. Use of fluoroquinolones with corticosteroids should also be avoided as it may exacerbate fluoroquinolone-induced tendinitis and tendon rupture. Fluoroquinolones should be prescribed with caution in patients older than 60 years and in patients with renal impairment or solid-organ transplants as they are at a higher risk of tendon injury.

MHRA/CHM advice: Fluoroquinolone antibiotics: new restrictions and precautions for use due to very rare reports of disabling and potentially long-lasting or irreversible side effects (March 2019)

With intravenous use or oral use in children:

Fluoroquinolones should be avoided in patients who have previously had serious adverse reactions. Use of fluoroquinolones with corticosteroids should also be avoided as it may exacerbate fluoroquinolone-induced tendinitis and tendon rupture. Fluoroquinolones should be prescribed with caution in patients with renal impairment or solid-organ transplants as they are at a higher risk of tendon injury.

MHRA/CHM advice: Systemic and inhaled fluoroquinolones: small risk of heart valve regurgitation; consider other therapeutic options first in patients at risk (December 2020)

With intravenous use or oral use or when used by inhalation in adults:

A European review of worldwide data found an increased risk of heart valve regurgitation associated with systemic and inhaled fluoroquinolones. A case-control study suggested a two-fold increased relative risk with current oral fluoroquinolone use compared with amoxicillin or azithromycin use.

Healthcare professionals are advised that fluoroquinolones are authorised for use in serious, life-threatening bacterial infections, and should only be used after careful benefit-risk assessment and consideration of other therapeutic options in patients with the following risk factors:

congenital or pre-existing heart valve disease;
connective tissue disorders (e.g. Marfan syndrome or Ehlers-Danlos syndrome);
other risk factors or conditions predisposing to heart valve regurgitation (e.g. hypertension, Turner’s syndrome, Behçet’s disease, rheumatoid arthritis, and infective endocarditis).

Patients should be advised to seek immediate medical attention if they experience a rapid onset of shortness of breath (especially when lying down flat in bed), swelling of the ankles, feet, or abdomen, or new-onset heart palpitations.

MHRA/CHM advice: Systemic and inhaled fluoroquinolones: small risk of heart valve regurgitation; consider other therapeutic options first in patients at risk (December 2020)

With intravenous use or oral use in children:

congenital or pre-existing heart valve disease;
connective tissue disorders (e.g. Marfan syndrome or Ehlers-Danlos syndrome);
other risk factors or conditions predisposing to heart valve regurgitation (e.g. hypertension, Turner’s syndrome, Behçet’s disease, rheumatoid arthritis, and infective endocarditis).

Contra-indications

Contra-indications For all quinolones

When used by inhalation

History of tendon disorders related to quinolone use

With intravenous use

History of tendon disorders related to quinolone use

With oral use

History of tendon disorders related to quinolone use

Cautions

Cautions For all quinolones

When used by inhalation

Can prolong the QT interval; conditions that predispose to seizures; diabetes (may affect blood glucose); exposure to excessive sunlight and UV radiation should be avoided during treatment and for 48 hours after stopping treatment; G6PD deficiency; history of epilepsy; myasthenia gravis (risk of exacerbation); psychiatric disorders

With intravenous use

Can prolong the QT interval; children or adolescents (arthropathy has developed in weight-bearing joints in young animals) (in children); conditions that predispose to seizures; diabetes (may affect blood glucose); exposure to excessive sunlight and UV radiation should be avoided during treatment and for 48 hours after stopping treatment; G6PD deficiency; history of epilepsy; myasthenia gravis (risk of exacerbation); psychiatric disorders

With oral use

Cautions, further information

Use in children

With intravenous use or oral use in children:

Quinolones cause arthropathy in the weight-bearing joints of immature animals and are therefore generally not recommended in children and growing adolescents. However, the significance of this effect in humans is uncertain and in some specific circumstances use of ciprofloxacin may be justified in children.

Cautions For ciprofloxacin

When used by ear

Known (or at risk of) perforated tympanic membrane

With intravenous use

Acute myocardial infarction (risk factor for QT interval prolongation); avoid excessive alkalinity of urine (risk of crystalluria); bradycardia (risk factor for QT interval prolongation); congenital long QT syndrome (risk factor for QT interval prolongation); electrolyte disturbances (risk factor for QT interval prolongation); ensure adequate fluid intake (risk of crystalluria); heart failure with reduced left ventricular ejection fraction (risk factor for QT interval prolongation); history of symptomatic arrhythmias (risk factor for QT interval prolongation)

With oral use

Interactions

View interactions for ciprofloxacin

Side-effects

Side-effects For all quinolones

Common or very common

Appetite decreased; arthralgia; asthenia; constipation; diarrhoea; dizziness; dyspnoea; eye discomfort; eye disorders; fever; fungal infection; gastrointestinal discomfort; headache; myalgia; nausea; QT interval prolongation; skin reactions; sleep disorders; taste altered; tinnitus; vision disorders; vomiting

Uncommon

Altered smell sensation; anaemia; anxiety; arrhythmias; chest pain; confusion; cough; depression; drowsiness; dry eye; eosinophilia; eye inflammation; flatulence; hallucination; hearing impairment; hepatic disorders; hyperglycaemia; hyperhidrosis; hypersensitivity; hypoglycaemia; hypotension; leucopenia; muscle weakness; neutropenia; pain; palpitations; peripheral neuropathy (sometimes irreversible); pseudomembranous enterocolitis (in adults); renal impairment; seizure; sensation abnormal; stomatitis; tendon disorders; thrombocytopenia; tremor; vertigo

Rare or very rare

Agranulocytosis; angioedema; arthritis; coordination abnormal; gait abnormal; haemolytic anaemia; idiopathic intracranial hypertension; myasthenia gravis aggravated; pancreatitis; photosensitivity reaction; polyneuropathy; psychotic disorder; severe cutaneous adverse reactions (SCARs); suicidal behaviours; syncope; vasculitis

Frequency not known

Heart valve incompetence; hypoglycaemic coma; increased risk of aortic aneurysm (more common in elderly); increased risk of aortic dissection (more common in elderly); rhabdomyolysis (in adults)

Side-effects, further information

The drug should be discontinued if neurological, psychiatric, tendon disorders or hypersensitivity reactions (including severe rash) occur. For more information regarding the safety of fluoroquinolones, please see Important Safety Information.

Side-effects For ciprofloxacin

Common or very common

When used by eye (topical)

Corneal deposits (reversible after completion of treatment)

With intravenous use

Arthropathy (in children)

With oral use

Arthropathy (in children)

Uncommon

When used by ear

Ear pruritus

With intravenous use

Akathisia; fungal superinfection; oedema; thrombocytosis; vasodilation

With oral use

Akathisia; fungal superinfection

Rare or very rare

When used by eye (topical)

Ear pain; increased risk of infection; paranasal sinus hypersecretion

With intravenous use

Antibiotic associated colitis; asthma; bone marrow disorders; crystalluria; erythema nodosum; haematuria; intracranial pressure increased; leucocytosis; migraine; muscle cramps; muscle tone increased; nephritis tubulointerstitial; olfactory nerve disorder; status epilepticus

With oral use

Frequency not known

With intravenous use

Mood altered; self-injurious behaviour

With oral use

Mood altered; self-injurious behaviour

Allergy and cross-sensitivity

Allergy and cross-sensitivity For all quinolones

Use of quinolones contraindicated in quinolone hypersensitivity.

Pregnancy

Pregnancy For all quinolones

With intravenous use or oral use or when used by inhalation:

Avoid in pregnancy—shown to cause arthropathy in animal studies; safer alternatives are available.

Pregnancy For ciprofloxacin

With intravenous use or oral use:

A single dose of ciprofloxacin may be used for the prevention of a secondary case of meningococcal meningitis.

When used by eye:

Manufacturer advises use only if potential benefit outweighs risk.

Breast feeding

Breast feeding For ciprofloxacin

When used by eye:

Manufacturer advises caution.

With intravenous use or oral use:

Amount too small to be harmful but manufacturer advises avoid.

Renal impairment

Renal impairment For ciprofloxacin

Dose adjustments

With oral use in adults:

Give 250–500 mg every 12 hours if eGFR 30–60 mL/minute/1.73 m² (every 24 hours if eGFR less than 30 mL/minute/1.73 m²).

With intravenous use in adults:

Give (200 mg over 30 minutes), 200–400 mg every 12 hours if eGFR 30–60 mL/minute/ 1.73m² (every 24 hours if eGFR less than 30 mL/ minute/1.73 m²).

With intravenous use or oral use in children:

Reduce dose if estimated glomerular filtration rate less than 30 mL/minute/1.73 m²—consult product literature.

Prescribing and dispensing information

Prescribing and dispensing information For ciprofloxacin

For choice of antibacterial therapy, see Antibacterials, use for prophylaxis, Anthrax, Ear infections, antibacterial therapy, Gastro-intestinal system infections, antibacterial therapy, Genital system infections, antibacterial therapy, Respiratory system infections, antibacterial therapy, Urinary-tract infections.

In adults:

For choice of antibacterial therapy, see Diabetic foot infections, antibacterial therapy.

Handling and storage

Handling and storage For ciprofloxacin

When used by ear:

Manufacturer advises discard any ampoules remaining 8 days after opening the pouch.

Patient and carer advice

Patient and carer advice For all quinolones

With intravenous use or oral use or when used by inhalation in adults:

The MHRA has produced an advice sheet on serious adverse reactions affecting musculoskeletal and nervous systems associated with fluoroquinolone use, which should be provided to patients and their carers.

With intravenous use or oral use in children:

Patient and carer advice For ciprofloxacin

Granules present in the oral suspension should not be chewed.

Medicines for Children leaflet: Ciprofloxacin drops for infection

When used by ear in children:

Medicines for Children leaflet: Ciprofloxacin for bacterial infection

With systemic use in children:

Driving and skilled tasks

With intravenous use or oral use:

May impair performance of skilled tasks (e.g. driving); effects enhanced by alcohol.

National funding/access decisions

National funding/access decisions For ciprofloxacin

For full details see funding body website.

Scottish Medicines Consortium (SMC) decisionsFor ciprofloxacin

SMC No. 1320/18

Ciprofloxacin (Cetraxal®) for the treatment of acute otitis externa in adults and children older than 1 year with an intact tympanic membrane, caused by ciprofloxacin susceptible microorganisms (April 2018)

Funding decision:

Recommended with restrictions

All Wales Medicines Strategy Group (AWMSG) decisionsFor ciprofloxacin

AWMSG No. 1343

Funding decision:

Recommended

Medicinal forms

There can be variation in the licensing of different medicines containing the same drug.

Forms available from special-order manufacturers include: oral suspension, ear drops, eye drops, eye ointment.

View all medicinal forms and pricing information

Or jump straight to:

Tablet
Oral suspension
Infusion
Solution for infusion
Ear drops
Eye drops

Question 76

Desferal Vials, 500mg

Summary of Product Characteristics Updated 06-Aug-2020 | Novartis Pharmaceuticals UK Ltd

1. Name of the medicinal product
2. Qualitative and quantitative composition
3. Pharmaceutical form
4. Clinical particulars
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. Pharmacological properties
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. Pharmaceutical particulars
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text

1. Name of the medicinal product

Desferal^® Vials, 500mg.

2. Qualitative and quantitative composition

Each vial contains desferrioxamine mesilate 500mg.

3. Pharmaceutical form

A sterile, lyophilised powder available in vials containing 500mg of desferrioxamine mesilate.

4. Clinical particulars

4.1 Therapeutic indications

Treatment for chronic iron overload, e.g.

• transfusional haemosiderosis in patients receiving regular transfusions e.g. thalassaemia major

• primary and secondary haemochromatosis in patients in whom concomitant disorders (e.g. severe anaemia, hypoproteinaemia, renal or cardiac failure) preclude phlebotomy.

Treatment for acute iron poisoning.

For the diagnosis of iron storage disease and certain anaemias.

Aluminium overload – In patients on maintenance dialysis for end stage renal failure where preventative measures (e.g. reverse osmosis) have failed and with proven aluminium-related bone disease and/or anaemia, dialysis encephalopathy; and for diagnosis of aluminium overload.

4.2 Posology and method of administration

Desferal may be administered parenterally.

For parenteral administration:

The drug should preferably be employed in the form of a 10% solution, e.g. 500 mg: by dissolving the contents of one 500mg vial in 5ml of water for injection. When administered subcutaneously the needle should not be inserted too close to the dermis. The 10% Desferal solution can be diluted with routinely employed infusion solutions (saline, glucose, dextrose or dextrose-saline), although these should not be used as solvent for the dry substance. Dissolved Desferal can also be added to dialysis fluid and given intraperitoneally to patients on continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD).

Only clear pale yellow Desferal solutions should be used. Opaque, cloudy or discoloured solutions should be discarded. Heparin is pharmaceutically incompatible with Desferal solutions.

Treatment of acute iron poisoning

Adults and children:

Desferal may be administered parenterally. Desferal is an adjunct to standard measures generally used in treating acute iron poisoning. It is important to initiate treatment as soon as possible.

Parenteral Desferal treatment should be considered in any of the following situations:

• all symptomatic patients exhibiting more than transient minor symptoms (e.g. more than one episode of emesis or passage of one soft stool),

• patients with evidence of lethargy, significant abdominal pain, hypovolaemia, or acidosis,

• patients with positive abdominal radiograph results demonstrating multiple radio-opacities (the great majority of these patients will go on to develop symptomatic iron poisoning),

• any symptomatic patient with a serum iron level greater than 300 to 350 micro g/dL regardless of the total iron binding capacity (TIBC). It has also been suggested that a conservative approach without Desferal therapy or challenge should be considered when serum iron levels are in the 300 to 500 micro g/dL range in asymptomatic patients, as well as in those with self-limited, non-bloody emesis or diarrhoea without other symptoms.

The dosage and route of administration should be adapted to the severity of the poisoning.

Dosage:

The continuous intravenous administration of Desferal is the preferred route and the recommended rate for infusion is 15 mg/kg per hour and should be reduced as soon as the situation permits, usually after 4 to 6 hours so that the total intravenous dose does not exceed a recommended 80 mg/kg in any 24 hour period.

However, if the option to infuse intravenously is not available and if the intramuscular route is used the normal dosage is 2 g for an adult and 1g for a child, administered as a single intramuscular dose.

The decision to discontinue Desferal therapy must be a clinical decision; however, the following suggested criteria are believed to represent appropriate requirements for the cessation of Desferal. Chelation therapy should be continued until all of the following criteria are satisfied:

• the patient must be free of signs and symptoms of systemic iron poisoning (e.g. no acidosis, no worsening hepatoxicity),

• ideally, a corrected serum iron level should be normal or low (when iron level falls below 100 micro g/dL). Given that laboratories cannot measure serum iron concentrations accurately in the presence of Desferal, it is acceptable to discontinue Desferal when all other criteria are met if the measured serum iron concentration is not elevated.

• Repeat abdominal radiograph test should be obtained in patients who initially demonstrated multiple radio-opacities to ensure they have disappeared before Desferal is discontinued because they serve as a marker for continued iron absorption,

• If the patient initially developed vin-rose coloured urine with Desferal therapy, it seems reasonable that urine colour should return to normal before halting Desferal (absence of vin-rose urine is not sufficient by itself to indicate discontinuation of Desferal).

The effectiveness of treatment is dependent on an adequate urine output in order that the iron complex (ferrioxamine) is excreted from the body. Therefore if oliguria or anuria develop, peritoneal dialysis or haemodialysis may become necessary to remove ferrioxamine.

It should be noted that the serum iron level may rise sharply when the iron is released from the tissues.

Theoretically 100 mg Desferal can chelate 8.5 mg of ferric iron.

Chronic Iron Overload

The main aim of therapy in well-controlled patients is to maintain an iron balance and prevent haemosiderosis, whilst in overloaded patients a negative iron balance is desirable in order to deplete the increased iron stores and to prevent the toxic effects of iron.

Adults and children:

Desferal therapy should be commenced after the first 10- 20 blood transfusions, or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1000 ng/mL. The dose and mode of administration should be individually adapted according to the degree of iron overload.

Growth retardation may result from iron overload or excessive Desferal doses. If chelation is started before 3 years of age growth must be monitored carefully and the mean daily dose should not exceed 40mg/kg. (see section 4.4 Special warnings and precautions for use).

Dose:

The lowest effective dose should be used. The average daily dose will probably lie between 20 and 60 mg/kg/day. Patients with serum ferritin levels of < 2000 ng/mL should require about 25 mg/kg/day, and those with levels between 2000 and 3000 ng/mL about 35 mg/kg/day. Higher doses should only be employed if the benefit for the patient outweighs the risk of unwanted effects.

Patients with higher serum ferritin may require up to 55 mg/kg/day. It is inadvisable to regularly exceed an average daily dose of 50 mg/kg/day except when very intensive chelation is needed in patients who have completed growth. If ferritin values fall below 1000 ng/mL, the risk of Desferal toxicity increases; it is important to monitor these patients particularly carefully and perhaps to consider lowering the total weekly dose.

To assess the chelation therapy, 24 hour urinary iron excretion should initially be monitored daily. Starting with a dose of 500 mg daily the dose should be raised until a plateau of iron excretion is reached. Once the appropriate dose has been established, urinary iron excretion rates can be assessed at intervals of a few weeks.

Alternatively the mean daily dose may be adjusted based on ferritin level in order to keep the therapeutic index below 0.025 (i.e. the mean daily dose (mg/kg) of Desferal divided by the serum ferritin level (micro g/L) should be below 0.025). The therapeutic index is a valuable tool in protecting the patient from excess chelation, but it is not a substitute for careful clinical monitoring.

Mode of administration:

Slow subcutaneous infusion using a portable, light-weight, infusion pump over a period of 8-12 hours is effective and particularly convenient for ambulant patients. It may be possible to achieve a further increase in iron excretion by infusing the same daily dose over a 24 hour period. Desferal should normally be used with the pump 5-7 times a week. Desferal is not formulated to support subcutaneous bolus injection.

Since the subcutaneous infusions are more effective, intramuscular injections are given only when subcutaneous infusions are not feasible.

Elderly

Clinical studies of Desferal did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently compared to younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy’ (see sections 4.4 Special warnings and precautions for use and 4.8 Undesirable effects).

Hepatic impairment

No studies have been performed in patients with hepatic impairment.

Intravenous infusion during blood transfusion

The availability of an intravenous line during blood transfusions makes it possible to administer an intravenous infusion, e.g. in patients who comply poorly with and/or do not tolerate subcutaneous infusions.

The Desferal solution should not be put directly into the blood bag but may be added to the blood line by means of a “Y” adaptor located near to venous site of injection. The patient’s pump should be used to administer Desferal as usual. Because of the limited amount of drug that can be administered by IV infusion during blood transfusion, the clinical benefit of this mode of administration is limited. Patients and nurses should be warned against accelerating the infusion, as an intravenous bolus of Desferal may lead to flushing, hypotension and circulatory collapse (see section 4.4 Special warnings and precautions for use).

Continuous intravenous infusion is recommended for patients incapable of continuing subcutaneous infusions and in those who have cardiac problems secondary to iron overload. 24 hour urinary iron excretion should be measured regularly where intensive chelation (i.v.) is required, and the dose adjusted accordingly. Implanted intravenous systems can be used when intensive chelation is carried out.

Care should be taken when flushing the line to avoid a sudden infusion of residual Desferal which may be present in the dead space of the line, as this may lead to flushing, hypotension and circulatory collapse (see section 4.4 Specialwarnings and precautionsfor use).

Diagnosis of iron storage disease and certain anaemias

The Desferal test for iron overload is based on the principle that normal subjects do not excrete more than a fraction of a milligram of iron in their urine daily, and that a standard intramuscular injection of 500 mg of Desferal will not increase this above 1 mg of iron (18 micro mol). In iron storage diseases, however, the increase may be well over 1.5 mg (27 micro mol). It should be borne in mind that the test only yields reliable results when renal function is normal.

Desferal is administered as 500 mg intramuscular injection. Urine is then collected for a period of 6 hours and its iron content determined.

Excretion of 1-1.5 mg (18-27 micro mol) of iron during this 6-hour period is suggestive of iron overload; values greater than 1.5 mg (27 micro mol) can be regarded as pathological.

Treatment for aluminium overload in patients with end stage renal failure

Patients should receive Desferal if:

– they have symptoms or evidence of organ impairment due to aluminium overload

– they are asymptomatic but their serum aluminium levels are consistently above 60 ng/mL and associated with a positive Desferal test (see below), particularly if a bone biopsy provides evidence of aluminium related bone disease.

The iron and aluminium complexes of Desferal are dialysable. In patients with renal failure their elimination will be increased by dialysis.

Adults and children:

Patients on maintenance haemodialysis or haemofiltration: 5 mg/kg once a week. Patients with post-desferrioxamine test serum aluminium levels up to 300 ng/mL: Desferal should be given as a slow i.v. infusion during the last 60 minutes of a dialysis session (to reduce loss of free drug in the dialysate). Patients with a post-desferrioxamine test serum aluminium value above 300 ng/ml: Desferal should be administered by slow i.v. infusion 5 hours prior to the dialysis session.

Four weeks after the completion of a three month course of Desferal treatment a Desferal infusion test should be performed, followed by a second test 1 month later. Serum aluminium increases of less than 50ng/mL above baseline measured in 2 successive infusion tests indicate that further Desferal treatment is not necessary.

Patients on CAPD or CCPD:

5 mg/kg once a week prior to the final exchange of the day. It is recommended that the intraperitoneal route be used in these patients. However, Desferal can also be given i.m., by slow infusion i.v. or s.c.

Diagnosis of aluminium overload in patients with end stage renal failure

A Desferal infusion test is recommended in patients with serum aluminium levels > 60ng/mL associated with serum ferritin levels >100 ng/mL.

Just before starting the haemodialysis session, a blood sample is taken to determine the baseline level serum aluminium level.

During the last 60 minutes of the haemodialysis session a 5mg/kg dose is given as a slow intravenous infusion.

At the start of the next haemodialysis session (i.e. 44 hours after the aforementioned Desferal infusion) the second blood sample is taken to determine the serum aluminium level once more.

An increase in serum aluminium above baseline of more than 150 ng/mL is suggestive of aluminium overload. It should be noted that a negative test does not completely exclude the possibility of aluminium overload.

Theoretically 100 mg Desferal can bind 4.1 mg Al⁺⁺⁺.

Use in the elderly

No special dosage regime is necessary but concurrent renal insufficiency should be taken into account.

4.3 Contraindications

Hypersensitivity to desferrioxamine mesilate unless the patients can be desensitised.

4.4 Special warnings and precautions for use

Renal impairment

Desferal should be used with caution in patients with renal impairment since the metal complexes are excreted via the kidneys. In these patients, dialysis will increase the elimination of chelated iron and aluminium. Isolated cases of acute renal failure have been reported (see also section 4.8 Undesirable effects). Monitoring patients for changes in renal function (e.g. increased serum creatinine) should be considered.

Neurological impairment

Used alone Desferal may exacerbate neurological impairment in patients with aluminium-related encephalopathy. This deterioration (manifest as seizures) is probably related to an acute increase in brain aluminium secondary to elevated circulating levels. Pretreatment with clonazepam has been shown to afford protection against such impairment. Also, treatment of aluminium overload may result in decreased serum calcium and aggravation of hyperparathyroidism.

Rapid intravenous infusion

Treatment with Desferal by the intravenous route should only be administered in the form of slow infusions. Rapid intravenous infusion may lead to hypotension and shock (e.g. flushing, tachycardia, circulatory collapse and urticaria).

Instructions for use and handling

Desferal should not be administered s.c. in concentrations and/or doses higher than those recommended as local irritation at the site of administration may occur more frequently.

Infections

Patients suffering from iron overload are particularly susceptible to infection. There have been reports of Desferal promoting some infections such as Yersinia enterocolitica and Y. pseudotuberculosis. If patients develop fever with pharyngitis, diffuse abdominal pain or enteritis/enterocolitis, Desferal therapy should be stopped, and appropriate treatment with antibiotics should be instituted. Desferal therapy may be resumed once the infection has cleared.

In patients, receiving Desferal for aluminium and/or iron overload there have been rare reports of mucormycosis (a severe fungal infection), some with fatal outcome. If any characteristic signs or symptoms occur Desferal treatment should be discontinued, mycological tests carried out and appropriate treatment immediately instituted. Mucormycosis has been reported to occur in dialysis patients not receiving Desferal, thus no causal link with the use of the drug has been established.

Visual and hearing impairment

Disturbances of vision and hearing have been reported during prolonged Desferal therapy. In particular, this has occurred in patients on higher than recommended therapy or in patients with low serum ferritin levels. Patients with renal failure who are receiving maintenance dialysis and have low ferritin levels may be particularly prone to adverse reactions, visual symptoms having been reported after single doses of Desferal. Therefore, ophthalmological and audiological tests should be carried out both prior to the institution of therapy with Desferal and at 3-monthly intervals during treatment particularly if ferritin levels are low. By keeping the ratio of the mean daily dose (mg/kg of Desferal) divided by the serum ferritin (micro g/L) below 0.025 the risk of audiometric abnormalities may be reduced in thalassaemia patients. A detailed ophthalmological assessment is recommended (visual field measurements, fundoscopy, and colour vision testing using pseudoisochromatic plates and the Farnsworth D-15 colour test, slit lamp investigation, visual evoked potential studies).

If disturbances of vision or hearing do occur, treatment with Desferal should be stopped. Such disturbances are usually reversible. If Desferal therapy is re-instituted later at a lower dosage, close monitoring of ophthalmological/auditory function should be carried out with due regard to the risk-benefit ratio.

Paediatrics: growth retardation

The use of inappropriately high doses of Desferal in patients with low ferritin levels or young children (<3 years at commencement of treatment) has also been associated with growth retardation; dose reduction has been found to restore the growth rate to pretreatment levels in some cases. Three monthly checks on body weight and height are recommended in children.

Growth retardation if associated with excessive doses of Desferal must be distinguished from growth retardation from iron overload. Growth retardation from Desferal use is rare if the dose is kept below 40 mg/kg; if growth retardation has been associated with doses above this value, then reduction of the dose may result in return in growth velocity, however, predicted adult height is not attained.

Acute respiratory distress syndrome

Acute respiratory distress syndrome has been described following treatment with excessively high i.v. doses of Desferal in patients with acute iron intoxication, and also in thalassaemic patients (see section 4.8 Undesirable effects). The recommended daily doses should therefore not be exceeded.

It should be noted that desferrioxamine will affect aluminium levels and may necessitate some dosage adjustment of erythropoietin if co-prescribed.

4.5 Interaction with other medicinal products and other forms of interaction

Oral administration of vitamin C (up to a maximum of 200 mg daily, given in divided doses) may serve to enhance excretion of the iron complex in response to Desferal; larger doses of vitamin C fail to produce an additional effect. Monitoring of cardiac function is indicated during such combined therapy. Vitamin C should be given only if the patient is receiving Desferal regularly and should not be administered within the first month of Desferal therapy. In patients with severe chronic iron-storage disease undergoing combined treatment with Desferal and high doses of vitamin C (more than 500 mg daily) impairment of cardiac function has been encountered; this proved reversible when the vitamin C was withdrawn. Vitamin C supplements should not, therefore, be given to patients with cardiac failure.

Desferal should not be used in combination with prochlorperazine (a phenothiazine derivative) since prolonged unconsciousness may result.

Gallium⁶⁷ imaging results may be distorted because of the rapid urinary excretion of Desferal-bound radiolabel. Discontinuation of Desferal 48 hours prior to scintigraphy is advised.

4.6 Pregnancy and lactation

Women of child-bearing potential

In women of child-bearing potential, each case the benefits for the mother must be weighed against the risks for the child.

Pregnancy

There is a limited amount of data on the use of desferrioxamine in pregnant patients. Studies in animals (rabbits) have shown reproductive toxicity/teratogenicity (see section 5.3 Preclinical safety data). The risk to the foetus/mother is unknown.

Desferal should be used during pregnancy only if the expected benefits to the mother outweigh the potential risk to the foetus.

Breastfeeding

It is not known whether Desferal is excreted into the breast milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse drug reactions in breast-fed newborns/infants, a decision should be made whether to abstain from breast-feeding or to abstain from using the medicinal product, taking into account the importance of the medicinal product to the mother.

4.7 Effects on ability to drive and use machines

Patients experiencing CNS effects such as dizziness or impaired vision or hearing should be warned against driving or operating machinery.

4.8 Undesirable effects

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to ≤ 1/100); rare (≥ 1/10,000 to ≤ 1/1,000); very rare (≤ 1/10,000) including isolated reports; not known (cannot be estimated from the available data).

Some signs and symptoms reported as adverse effects may also be manifestations of the underlying disease (iron and/or aluminium overload).

Table 1

Infections and infestationsRare: Mucormycosis infections have been reported (see 4.4 Special warnings and precautions for use).Very rare: Gastroenteritisyersinia infections have been reported (see 4.4 Special warnings and precautions for use).Blood and lymphatic system disordersVery rare: blood disorders including thrombocytopeniaUnknown: leukopeniaImmune system disordersVery rare: anaphylactic shock, anaphylactic reactions, angioneurotic oedema.Nervous system disordersVery rare: neurological disturbances, including dizziness, precipitation or exacerbation of aluminium-related dialysis encephalopathy, neuropathy peripheral, paraesthesia (see 4.4 Special warnings and precautions for use).Unknown: convulsion.Eye disordersRare: loss of vision, scotoma, retinal degeneration, optic neuritis, cataracts (visual acuity decreased), blurred vision, night blindness, visual field defects, chromatopsia (impairment of colour vision), corneal opacities, (see 4.4. Special warnings and precautions for use). Eye disorders are rare, except if high doses are given.Ear and labyrinth disordersUncommon: deafness neurosensory, tinnitus (see 4.4. Special warnings and precautions for use). Keeping within dose guidelines helps minimise risk of hearing side effects.Vascular disordersRare: hypotension, tachycardia and shock if precautions for administration are not adhered to (see 4.2 Posology and method of administration and 4.4 Special warnings and precautionsfor use).Respiratory, thoracic and mediastinal disordersVery rare: acute respiratory distress lung infiltration (see 4.4 Special warnings and precautions for use).Gastrointestinal disordersVery rare: diarrhoea.Skin and subcutaneous tissue disordersVery rare: rash generalised.Musculoskeletal and connective tissue disordersCommon: growth retardation and bone disorder (e.g. metaphyseal dysplasia) are common in chelated patients given doses of 60 mg/kg, especially those who begin iron chelation in the first three years of life. If doses are kept to 40 mg/kg or below, the risk is considerably reduced (see 4.4 Special warnings and precautions for use).Unknown: muscle spasms.Renal and urinary disordersUnknown: acute renal failure, renal tubular disorder, blood creatinine increased (see 4.4 Special warnings and precautions for use and section 4.9 Overdose).

Special remarks

At the injection site pain, swelling, infiltration, erythema, pruritus and eschar/crust are very common; vesicles, local oedema and burning are uncommon reactions. The local manifestations may be accompanied by systemic reactions like arthralgia/myalgia (very common), headache (common), urticaria (common), nausea (common), pyrexia (common), vomiting (uncommon), or abdominal pain (uncommon) or asthma (uncommon).

Excretion of the iron complex may cause reddish-brown discoloration of the urine.

Convulsion has been mainly reported in dialysed patients with aluminium overload.

Patients treated for chronic aluminum overload

Desferal chelation therapy aluminum overload may result in hypocalcemia and aggravation of hyperparathyroidism (see section 4.4 Special warnings and precautions for use).

Reporting of suspected adverse reactions

4.9 Overdose

Desferal is usually administered parenterally and acute poisoning is unlikely to occur.

Signs and symptoms: tachycardia, hypotension and gastro-intestinal symptoms have occasionally occurred in patients who received an overdose of Desferal. Accidental administration of Desferal by the i.v. route may be associated with acute but transient loss of vision, aphasia, agitation, headache, nausea, bradycardia, hypotension and acute renal failure (see section 4.8 Undesirable effects).

Acute respiratory distress syndrome has been described following treatment with excessively high i.v. doses of Desferal in patients with acute iron intoxication, and also in thalassemic patients (see also section 4.4 Special warnings and precautions for use).

Treatment: there is no specific antidote to Desferal but signs and symptoms may be eliminated by reducing the dosage and Desferal is dialysable. Appropriate supportive therapy should be instituted.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Chelating agent (ATC code: V03AC01)

Desferal is a chelating agent for trivalent iron and aluminium ions; the resulting chelates (ferrioxamine and aluminoxamine) are stable and non-toxic. Neither chelate undergoes intestinal absorption, and any formed systemically as a result of parenteral administration is rapidly excreted via the kidneys without deleterious effects. Desferal takes up iron either free or bound to ferritin and haemosiderin. Similarly it mobilises and chelates tissue bound aluminium. It does not remove iron from haemin containing substances including haemoglobin and transferrin. Since both ferrioxamine and aluminoxamine are completely excreted, Desferal promotes the excretion of iron and aluminium in urine and faeces, thus reducing pathological iron or aluminium deposits in the organs and tissues.

5.2 Pharmacokinetic properties

Absorption

Desferrioxamine is rapidly absorbed after intramuscular bolus injection or slow subcutaneous infusion, but is only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa.

During peritoneal dialysis desferrioxamine is absorbed if administered in the dialysis fluid.

Distribution

In healthy volunteers peak plasma concentrations of desferrioxamine (15.5 micro mol/L (87 micro g/mL)) were measured 30 minutes after an intramuscular injection of 10 mg/kg desferrioxamine. One hour after injection the peak concentration of ferrioxamine was 3.7 micro mol/L (2.3 micro g/mL). Less than 10% of desferrioxamine is bound to serum proteins in vitro.

Biotransformation

Four metabolites of desferrioxamine were isolated from the urine of patients with iron overload. The following biotransformation reactions were found to occur with desferrioxamine: transamination and oxidation yielding an acid metabolite, beta-oxidation also yielding an acid metabolite, decarboxylation and N-hydroxylation yielding neutral metabolites.

Elimination

Both desferrioxamine and ferrioxamine a biphasic elimination after intramuscular injection in healthy volunteers; for desferrioxamine the apparent distribution half-life is 1 hour, and for ferrioxamine 2.4 hours. The apparent terminal half-life is 6 hours for both. Within six hours of injection, 22% of the dose appears in the urine as desferrioxamine and 1% as ferrioxamine.

Characteristics in patients

In patients with haemochromatosis peak plasma levels of 7.0 micro mol/L (3.9 micro g/mL) were measured for desferrioxamine, and 15.7 micro mol/L (9.6 micro g/mL) for ferrioxamine, 1 hour after an intramuscular injection of 10 mg/kg desferrioxamine. These patients eliminated desferrioxamine and ferrioxamine with half-lives of 5.6 and 4.6 hours respectively. Six hours after the injection 17% of the dose was excreted in the urine as desferrioxamine and 12% as ferrioxamine.

In patients dialysed for renal failure who received 40 mg/kg desferrioxamine infused i.v. within 1 hour, the plasma concentration at the end of the infusion was 152 micro mol/L (85.2 micro g/mL) when the infusion was given between dialysis sessions. Plasma concentrations of desferrioxamine were between 13% and 27% lower when the infusion was administered during dialysis. Concentrations of ferrioxamine were in all cases approximately 7.0 micro mol/L (4.3 micro g/mL) with concomitant aluminoxamine levels of 2-3 micro mol/litre (1.2-1.8 micro g/mL). After the infusion was discontinued, the plasma concentrations of desferrioxamine decreased rapidly with a half-life of 20 minutes. A smaller fraction of the dose was eliminated with a longer half-life of 14 hours. Plasma concentrations of aluminoxamine continued to increase for up to 48 hours post-infusion and reached values of approximately 7 micro mol/L (4 micro g/mL). Following dialysis the plasma concentration of aluminoxamine fell to 2.2 micro mol/L (1.3 micro g/mL), indicating that the aluminoxamine complex is dialysable.

In patients with thalassaemia continuous intravenous infusion of 50mg/kg/24h of desferrioxamine resulted in plasma steady state levels of desferrioxamine of 7.4 micro mol/L. Elimination of desferrioxamine from plasma was biphasic with a mean distribution half-life of 0.28 hours and an apparent terminal half-life of 3.0 hours. The total plasma clearance was 0.5 L/h/kg and the volume of distribution at steady state was estimated at 1.35 L/kg. Exposure to the main iron binding metabolite was around 54% of that of desferrioxamine in terms of AUC. The apparent monoexponential elimination half-life of the metabolite was 1.3 hours.

Clinical studies

Desferrioxamine was used as a comparator in a randomized, one-year clinical trial investigating the use of another iron chelator (deferasirox) in patients with beta-thalassemia and transfusional hemosiderosis. A total of 290 patients were treated with subcutaneous desferrioxamine at starting doses of 20 to 60 mg/kg for 5 days per week. The study showed a dose-dependent effect of desferrioxamine on serum ferritin levels, liver iron concentration and iron excretion rate.

Desferrioxamine was also used as a comparator in a second open-label, randomized, one-year trial investigating the use of deferasirox in patients with sickle cell disease and transfusional hemosiderosis. A total of 63 patients were treated with subcutaneous desferrioxamine at starting doses of 20 to 60 mg/kg at least 5 days per week. At the end of the study, the mean change in liver iron concentration (LIC) was -0.7 mg Fe/g dry weight.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical particulars

6.1 List of excipients

None present.

6.2 Incompatibilities

None known.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Vial: Do not store above 25°C

Reconstituted solution: Single use only.

From a microbiological point of view, the product should be used immediately after reconstitution (commencement of treatment within 3 hours). When the reconstitution is carried out under validated aseptic conditions the reconstituted solution may be stored for a maximum of 24 hours at room temperature (25°C or below) before administration. If not used immediately, in-use storage times and conditions prior to administration are the responsibility of the user. Unused solution should be discarded.

6.5 Nature and contents of container

Each vial contains a white to practically white lyophilisate supplied in a clear glass vial in a pack size of 10 (500 mg).

6.6 Special precautions for disposal and other handling

None stated.

7. Marketing authorisation holder

Novartis Pharmaceuticals UK Limited,

2nd Floor, The WestWorks Building,

White City Place,

195 Wood Lane,

London,

W12 7FQ

United Kingdom

8. Marketing authorisation number(s)

PL 00101/0523.

9. Date of first authorisation/renewal of the authorisation

31 October 1997 / 12 December 2000

10. Date of revision of the text

23 July 2020

LEGAL CATEGORY

POM

Company Contact Details

Novartis Pharmaceuticals UK Ltd

Address

2nd Floor, The WestWorks Building, White City Place, 195 Wood Lane, London, W12 7FQ

E-mail

novartis.customercare@novartis.com

Medical Information e-mail

medinfo.uk@novartis.com

Telephone

+44 (0)1276 692 255

Medical Information Direct Line

+44 (0)1276 698 370

Customer Care direct line

+44 (0)845 741 9442

Question 77-78

Trimethoprim 50 mg/5 ml Suspension

Summary of Product Characteristics Updated 12-Sep-2019 | Pinewood Healthcare

1. Name of the medicinal product
2. Qualitative and quantitative composition
3. Pharmaceutical form
4. Clinical particulars
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Fertility, pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. Pharmacological properties
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. Pharmaceutical particulars
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text

1. Name of the medicinal product

Trimethoprim 50 mg/5 ml Suspension

2. Qualitative and quantitative composition

Each 5 ml contains 50 mg of Trimethoprim Ph.Eur.

Excipients with known effect

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral suspension.

A white, opalescent, viscous suspension.

4. Clinical particulars

4.1 Therapeutic indications

Trimethoprim is indicated for the prevention and treatment of urinary tract infections in adults and children, and the treatment of other susceptible infections in adults and children caused by a wide range of trimethoprim sensitive Gm +ve and Gm -ve organisms including Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae, Staphylococcus aureus, E.coli, Enterobacter, Proteus and Streptococcus faecalis.

4.2 Posology and method of administration

Method of administration

For oral administration

Posology

Adults & Children over 12 years of age

Treatment of urinary tract infections and all other susceptible infections: 200 mg (20 ml) twice daily.

Long-term prevention of recurrent urinary tract infections: 100 mg (10 ml) at night.

Children 6 weeks to 12 years of age

Treatment of urinary tract infections is based on a dosage of 8 mg/kg body weight daily, subdivided into two equal doses. Suggested regimens are:

6 weeks – 5 months	–	25 mg (2.5 ml) twice daily
6 months – 5 years	–	50 mg (5 ml) twice daily
6 years – 12 years	–	100 mg (10 ml) twice daily

Long-term prevention of recurrent urinary tract infection is based on 2 mg/kg body weight daily given as a single dose at night. Suggested regimens are:

6 months – 5 years	–	25 mg (2.5 ml) at night
6 years – 12 years	–	50 mg (5 ml) at night

Dosage advised where there is reduced kidney function:

eGFR (ml/min)	Dosage advised
Over 30	Normal
15- 30	Normal for 3 days then half dose
Under 15	Half the normal dose

Monitoring of renal function and serum electrolytes should be considered particularly with longer term use, in patients with impaired renal function.

Trimethoprim should only be initiated and used in dialysis patients under close supervision from specialists in both infectious disease and renal medicine. Trimethoprim is removed by dialysis.

Monitoring trimethoprim plasma concentration may be considered with long term therapy but the value of this in individual cases should first be discussed with specialists in infectious disease and renal medicine.

Elderly

Depending on kidney function, see special dosage schedule.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Trimethoprim is contra-indicated in severe hepatic insufficiency.

Trimethoprim is contra-indicated in megaloblastic anaemia and other blood dyscrasias.

Trimethoprim should not be administered to pregnant women, premature infants or children under 4 months.

4.4 Special warnings and precautions for use

Care is necessary in administration to patients with impaired renal function.

Regular haematological tests should be performed during long term therapy.

In patients with renal impairment, care should be taken to avoid accumulation. Monitoring of renal function and serum electrolytes should be considered particularly with longer term use.

Trimethoprim should only be initiated and used in dialysis patients under close supervision from specialists in both infectious disease and renal medicine.

Trimethoprim may cause depression of haemopoiesis. Regular haematological tests should be undertaken in patients receiving long term treatment and those predisposed to folate deficiency, (e.g. the elderly), to check for possible pancytopaenia. If there is evidence of folic acid deficiency, calcium folinate should be administered and response checked by haematologic monitoring. It may be necessary to discontinue trimethoprim. Particular care should be exercised in the haematological monitoring of children on long term therapy.

Isolated cases of megaloblastic anaemia during prolonged therapy with trimethoprim in doses higher than those recommended have been reported but these are reversible with discontinuation of therapy and administration of calcium folinate.

If a patient has a known or suspected risk of acute prophyria, treatment with trimethoprim should be avoided.

Close monitoring of serum electrolytes is advised in patients at risk for hyperkalaemia (see section 4.8). Elevations in serum potassium have been observed in some patients treated with trimethoprim. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, poorly controlled diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, renin angiotensin system inhibitors (eg: ACE inhibitors or renin angiotensin receptor blockers), or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the above-mentioned agents is deemed appropriate, monitoring of serum potassium is recommended (see section 4.5).

Monitoring of blood glucose is advised if co-administered with repaglinide (see section 4.5).

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Folate antagonists and anticonvulsants: Trimethoprim may induce folate deficiency in patients predisposed to folate deficiency such as those receiving concomitant folate antagonists or anticonvulsants.

Bone marrow depressants: Trimethoprim may increase the potential for bone marrow aplasia.

Cytotoxics such as azathioprine, mercaptopurine, methotrexate, increase the risk of haematologic toxicity when given with trimethoprim. Special care is necessary in patients receiving pyrimethamine in addition to trimethoprim.

Phenytoin and Digoxin: Careful monitoring of patients treated with digoxin or phenytoin is advised as trimethoprim may increase plasma concentration of these agents by increasing their elimination half-life.

Rifampicin may decrease trimethoprim concentrations.

Diuretics: In elderly patients concurrently taking diuretics, primarily thiazides, there is an increased incidence of thrombocytopenia with purpura.

Concomitant use of drugs that may increase serum potassium levels may lead to a significant increase in serum potassium. Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, renin-angiotensin system inhibitors (eg: ACE inhibitors or renin angiotensin receptor blockers) and other potassium increasing substances (eg: heparin). Monitoring of potassium should be undertaken as appropriate (see section 4.4).

Ciclosporin: Increased risk of nephrotoxicitiy.

Procainamide: Trimethoprim increases plasma concentrations of procainamide.

Dapsone: Plasma concentrations of trimethoprim and dapsone may increase when taken together.

Repaglinide: Trimethoprim may enhance the hypoglycaemic effects of repaglinide.

Anticoagulants: Trimethoprim may potentate the anticoagulant effect of warfarin and other coumarins.

Antibacterials: Plasma concentration of trimethoprim is possibly reduced by rifampicin. Plasma concentration of both drugs may increase when trimethoprim is given with dapsone.

Antimalarials: Increased antifolate effect when trimethoprim is given with pyrimethamine.

4.6 Fertility, pregnancy and lactation

Pregnancy

Trimethoprim is contra-indicated in pregnant women, premature infants or infants during the first few weeks of life.

Breastfeeding

Trimethoprim is excreted in breast milk. Effects on the suckling child are likely if therapeutic doses are administered to breast-feeding mothers. Trimethoprim is contraindicated if the breast fed infant is less than 4 months of age.

4.7 Effects on ability to drive and use machines

Not known.

4.8 Undesirable effects

The following list of undesirable effects have been reported by healthcare professionals. Sometimes it may be difficult to distinguish reactions caused by the condition being treated from adverse drug reactions, which means that not all the listed reactions were caused by drug administration.

Infections and Infestations

Common: Monilial overgrowth

Blood and lymphatic system disorders

Very rare: Leucopenia, neutropenia, thrombocytopenia, pancytopaenia, bone marrow depression, agranulocytosis, aplastic anaemia, haemolytic anaemia, eosinophilia, purpura, haemolysis.

Unknown: Megaloblastic anaemia, methaemoglobinaemia, depression of haematopoiesis.

Fatalities have been reported (especially in the elderly, or those with impairment of renal or hepatic function in whom careful monitoring is advised- refer to Section 4.3 Contraindications), however the majority of haematological changes are mild and reversible when treatment is stopped.

Immune system disorders

Very rare: Hypersensitivity, anaphylaxis, angioedema, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus arythematosus.

Metabolism and nutrition disorders

Very common: Hyperkalaemia

Very rare: Hypoglycaemia, hyponatraemia, anorexia.

Close supervision is recommended when trimethoprim is used in elderly patients or in patients taking high doses as these patients may be more susceptible to hyperkalaemia and hyponatraemia.

Psychiatric disorders

Very rare: Depression, hallucinations, confusional states, agitation, anxiety, abnormal behaviour, insomnia and nightmares.

Nervous system disorders

Common: Headache

Very rare: Dyskinesias, aseptic meningitis, tremor, ataxia, dizziness, lethargy, syncope, paraesthesiae, convulsions, peripheral neuritis, vertigo, tinnitus.

Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either co-trimoxazole or to trimethoprim alone.

Eye disorders

Very rare: uveitis.

Respiratory, thoracic and mediastinal disorders

Very rare: Cough, shortness of breath, wheeze, epistaxis.

Gastrointestinal disorders

Common: Nausea, diarrhoea, vomiting.

Very rare: Constipation, glossitis, stomatitis, pseudomembranous colitis, pancreatitis. Unknown: Sore mouth, gastro-intestinal disturbance

Hepatobiliary disorders

Very rare: Elevation of serum transaminases, elevation of bilirubin levels, cholestatic jaundice, hepatic necrosis. Cholestatic jaundice and hepatic necrosis may be fatal.

Skin and subcutaneous tissue disorders

Common: Skin rashes, urticaria

Very rare: Photosensitivity, exfoliative dermatitis, fixed drug eruption, erythema multiforme, erythema nodusum, Stevens-Johnson Syndrome, toxic epidermal necrolysis, bullous dermatitis, purpura.

Unknown: Pruritis

Lyell’s syndrome (toxic epidermal necrolysis) carries a high mortality.

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia, myalgia and uveitis.

Renal and urinary disorders

Very rare: Impaired renal function (sometimes reported as renal failure), haematuria.

Reporting of suspected adverse reactions

4.9 Overdose

Treatment of overdosage: Symptomatic treatment, gastric lavage and forced diuresis can be used. Depression of haematopoiesis by trimethoprim can be counteracted by intramuscular administration of calcium folinate.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Systemic antibacterial, ATC code: J01EA01

Mechanism of action

Trimethoprim is a dihydrofolate reductase inhibitor, inhibiting the conversion of bacterial dihydrofolic acid to tetrahydrofolic acid, required for the synthesis of some amino acids.

Its effects are considerably greater on the cells of micro-organisms than on the mammalian cells. Trimethoprim may be bactericidal or bacteriostatic depending on growth conditions.

In vitro trimethoprim has effects on most Gram-positive and Gram-negative aerobic organisms, including enterobacteria such as E Coli, Proteus, Klebsiella pneumoniae, Streptococcus faecalis, Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus.

It has no effect on Mycobacterium tuberculosis, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Treponema pallidum, Brucella abortis or anaerobic bacteria.

Mechanism(s) of resistance

Resistance to trimethoprim may be due to several mechanisms. Clinical resistance is often due to plasmid mediated dihydrofolate reductases that are resistant to trimethoprim: such genes may become incorporated into the chromosome via transposons. Resistance may also be due to overproduction of dihydrofolate reductase, changes in cell permeability, or bacterial mutants which are intrinsically resistant to trimethoprim because they depend on exogenous thymidine and thymine for growth. Emergence of resistance to trimethoprim does not appear to be any higher in areas where it is used alone than in areas where trimethoprim is used in combination with sulphonamides.

Nonetheless, trimethoprim resistance has been reported in many species, and very high frequencies of resistance have been seen in some developing countries, particularly among Enterobacteriaceae.

EUCAST clinical MIC breakpoints to separate susceptible (S) pathogens from resistant (R) pathogens are:

EUCAST Species-related breakpoints (Susceptible≤/Resistant>) Units: mg/
Enterobacteriaceae	Staphylococcus	Enterococcus
≤2/>4	≤2/>4	≤0.032/>1*

*The activity of trimethoprim is uncertain against enterococci. Hence the wild type population is categorized as intermediate.

5.2 Pharmacokinetic properties

Trimethoprim is readily absorbed from the gastro-intestinal tract and peak concentrations in the circulation occur about 3 hours after a dose is taken. About 45% is bound to plasma proteins. Tissue concentrations are reported to be higher than serum concentrations with particularly high concentrations in the kidneys and lungs. Concentrations in the CSF are about half that of those in blood. The half life is about 10-16 hours. 40-50% of the dose is excreted unchanged in the urine within 24 hours.

5.3 Preclinical safety data

Pre-clinical information has not been included because the safety profile of trimethoprim has been established after many years of clinical use. Please refer to Section 4.

6. Pharmaceutical particulars

6.1 List of excipients

Sorbitol

Agar

Methyl hydroxybenzoate

Propyl hydroxybenzoate

Polysorbate 80

Saccharin Sodium

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months unopened.

6.4 Special precautions for storage

Store in the original container. Keep container in outer carton.

6.5 Nature and contents of container

Amber glass bottle with aluminium pilfer proof screw cap and expanded polyethylene liner.

Pack size: 100 ml.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Pinewood Laboratories Limited

Ballymacarbry

Clonmel

Co. Tipperary

Ireland

8. Marketing authorisation number(s)

PL 04917/0065

9. Date of first authorisation/renewal of the authorisation

15^th July 2005

10. Date of revision of the text

09^th September 2019

Company Contact Details

Pinewood Healthcare

Address

Ballymacarby, Clonmel, Co. Tipperary, Co. Tipperary, Ireland

Telephone

+353 52 6186000

Medical Information Direct Line

+44 1978 661 261

Medical Information Fax

+44 1978 661 702

WWW

home

Fax

+ 353 52 6136311

Medical Information e-mail

drug.safety@wockhardt.co.uk

Question 83

Question 84

Question 88

Package leaflet: Information for the user

BCG Vaccine AJV

Powder and solvent for suspension for injection.
Mycobacterium bovis BCG (Bacillus Calmette-Guerin), Danish strain 1331, live attenuated

Read all of this leaflet carefully before you or your child are vaccinated because it contains important information for you.
– Keep this leaflet. You may need to read it again.
– If you have any further questions, ask your doctor, pharmacist or nurse.

– This medicine has been prescribed for you or your child only. Do not pass it on to others.
– If you or your child get any side effects, talk to your doctor, pharmacist or nurse. This includes any

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What BCG Vaccine AJV is and what it is used for
2. What you need to know before you or your child are vaccinated with BCG Vaccine AJV 3. How you or your child are vaccinated with BCG Vaccine AJV
4. Possible side effects
5. How to store BCG Vaccine AJV
6. Contents of the pack and other information

1. What BCG Vaccine AJV is and what it is used for

BCG Vaccine AJV contains bacteria of the type Mycobacterium bovis BCG and is used for protection against tuberculosis (TB).

2. What you need to know before you or your child are vaccinated with BCG Vaccine AJV

You or your child should not be vaccinated with BCG Vaccine AJV

− If you have known allergies to any of the excipients in the vaccine (listed in section 6)
− If you are suffering from an acute severe febrile illness or generalised skin infection. In these cases

vaccination should be postponed
− If you have a weakened resistance toward infections due to a disease in/of your immune system − If you are receiving medical treatment that affects the immune response, e.g. corticosteroids or

radiotherapy
− If you have been exposed to immunosuppressive treatment in utero or via breast-feeding, (e.g. treatment

with TNF-α antagonists)
− If you are suffering from any malignant conditions, (e.g. lymphoma, leukaemia or Hodgkin’s disease) − If your immune status is in question
− If you are infected with HIV
− If you are receiving medical treatment against TB

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you or your child are vaccinated with BCG Vaccine AJV. The doctor or nurse will be extra cautious about vaccinating you or your child with BCG Vaccine AJV

− If you have eczema. The vaccination can be given in an eczema-free area 2

− If you have been skin tested for TB infection and the test was found positive vaccination is not required. Vaccination may cause a severe local reaction in that case

Other medicines and BCG Vaccine AJV

− Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines − Other vaccines can be given at the same time as BCG Vaccine AJV at different injection sites

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before being vaccinated with BCG Vaccine AJV.
Vaccination is not recommended during pregnancy or breast-feeding, although no harmful effects to the unborn or breastfed child have been associated with BCG Vaccine AJV.

Driving and using machines

BCG Vaccine AJV has no influence on the ability to drive and use machines.

BCG Vaccine AJV contains potassium and sodium

BCG Vaccine AJV contains less than 1 mmol potassium (39 mg) per dose, i.e. essentially ‘potassium-free’.

BCG Vaccine AJV contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.

3. How you or your child are vaccinated with BCG Vaccine AJV

The doctor or nurse will give the vaccination by injection into the upper layer of the skin.

The recommended dose is 0.05 ml for children under 12 months of age and 0.1 ml for adults and children aged 12 months or more.
The injection site is best left uncovered to facilitate healing.

The expected reactions to the vaccination include:
− a slight swelling, redness and tenderness at the injection site followed by a local lesion − some weeks later this lesion evolves into a small ulcer
− after some months this ulcer will heal leaving a small, flat scar
− a slight swelling of the lymph nodes in the armpit may be experienced

These are common reactions to the vaccination.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, BCG Vaccine AJV can cause side effects, although not everybody gets them.

Severe allergic reactions (such as redness of the face and neck, swelling of the face, throat or neck, skin rash, breathing difficulties and collapse) may occur in rare cases (less than 1 in 1,000).
If you observe any of the above reactions contact your doctor immediately.

Other side effects include:

Uncommon side effects (may affect up to 1 in 100 people)

− Fever

− Swelling of lymph nodes in the armpit larger than 1 cm across
− Inflammation of lymph nodes, sometimes with oozing ulcers and pus
− An oozing ulcer at the injection site
− Headache

Rare side effects (may affect up to 1 in 1,000 people)

− Abscess at the injection site
− Infection with the bacteria from the vaccine can occur. The infection can spread throughout the body,

including the bones
Fainting, seizures and convulsions among patients receiving injections have been observed.

In babies born very prematurely (at or before 28 weeks of gestation) longer gaps than normal between breaths may occur for 2-3 days after vaccination.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store BCG Vaccine AJV

− Keep this vaccine out of the sight and reach of children
− Store in a refrigerator (2 oC – 8 oC)
− Store in the original package in order to protect from light
− Do not freeze
− Do not use the vaccine after the expiry date which is stated on the carton as “EXP”
− The expiry date refers to the last day of that month

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What BCG Vaccine AJV contains

The active substance is:
Freeze-dried powder containing live attenuated bacteria of the type Mycobacterium bovis BCG (Bacillus Calmette-Guerin), Danish strain 1331. 1 ml vaccine contains between 2-8 million bacteria.

The other excipients are:
Sodium glutamate, magnesium sulphate heptahydrate, dipotassium phosphate, L-asparagine monohydrate, ferric ammonium citrate, glycerol 85%, citric acid monohydrate and water for injections.

What BCG Vaccine AJV looks like and contents of the pack

BCG Vaccine AJV consists of a powder and solvent for suspension for injection (2-8 x 105 bacteria/0.1 ml dose or 1-4 x 105 bacteria/0.05 ml dose). Pack sizes of 1, 5, or 10 vials and pack size of 1 vial with one syringe and two injection needles (one long for adding solvent and one short for intradermal injection). The powder in the amber vial is white and crystalline. The powder might be difficult to see due to the small amount of powder in the vial.

The solvent in the clear vial is a colourless solution without visible particles.
The mixed vaccine should appear as a homogenous, slightly opalescent, colourless suspension. Pack sizes: 1, 5, 10-vial packages and 1 vial enclosed in a 1-dose injection kit.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

AJ Vaccines A/S
5, Artillerivej
DK-2300 Copenhagen S
Denmark
tel.: +45 7229 7000
fax: +45 7229 7999
e-mail: ajvaccines@ajvaccines.com

This medicinal product is authorised in the Member States of the EEA under the following names:

DK: BCG Vaccine “AJ Vaccines” EL, FI: BCG Vaccine AJVaccines FR: VACCIN BCG AJVaccines NO: BCG-vaksine AJVaccines PL: BCG Szczepionka AJVaccines SE: BCG-vaccin AJVaccines

UK: BCG Vaccine AJV

This leaflet was last revised in 05/2018

The following information is intended for medical and healthcare professionals only

Special warnings and precautions for use

The vaccine should be administered strictly by the intradermal route.
The vaccine should preferably be administered by personnel trained in the intradermal vaccination technique. Inadequate administered injections, e.g. subcutaneously or intramuscularly increase the risk of lymphadenitis and abscess formation.
Tuberculin skin test positive persons should not be vaccinated as this may result in an aggravated loco- regional reaction.
Although anaphylactic reactions are rare, facilities for its management should always be available during vaccination.
Whenever possible, persons should be kept under observation for 15-20 minutes after vaccination, in case an allergic reaction should occur.
BCG vaccination may be given concurrently with inactivated or live vaccines, including combined measles, mumps and rubella vaccines. If not given concurrently, a period of not less than 4 weeks must pass before giving another live vaccine.
There must be an interval of at least 3 months before a vaccination in the same arm can take place.

Handling

The rubber stopper must not be wiped with any antiseptic or detergent. If alcohol is used to swab the rubber stopper, it must be allowed to evaporate before the stopper is penetrated with the syringe needle.
Using a syringe fitted with a long needle, transfer to the vial the volume of solvent stated on the label. Do not use other diluents as these may damage the vaccine.

Carefully invert the vial a few times to the resuspend the lyophilised BCG completely.
Do not shake the vial. Gently swirl the vial with the reconstituted vaccine before drawing up each subsequent dose.
When drawn up into the syringe, the reconstituted vaccine should appear homogeneous, slightly opaque and colourless.
When reconstituted, the vaccine should be used within 4 hours.

Method of administration

The vaccine should be administered by personnel trained in the intradermal technique.
The injection site should be clean and dry.
If antiseptics (such as alcohol) are applied to swab the skin, it must be allowed to evaporate before injection. The vaccine must be given strictly intradermally, approximately one third down the upper arm corresponding to the area of the distal insertion of the deltoid muscle, as follows:

− The skin is stretched between thumb and forefinger
− The needle should be almost parallel with the skin surface and slowly inserted (bevel upwards),

approximately 2 mm into the superficial layers of the dermis. The needle should be visible through the

epidermis during insertion

− The vaccine should be given slowly
− A raised, blanched papule at the needle point is a sign of correct injection
− The injection site is best left uncovered to facilitate healing

The mixed vaccine should be administered with a syringe of 1 ml graduated into hundredths of millilitre (1/100) fitted with a short bevel syringe needle (25G or 26G).
Jet injectors or multiple puncture devices should not be used to administer the vaccine.

Over dosage or incorrect administration

Overdose increases the risk of suppurative lymphadenitis and may lead to excessive scar formation. Gross over dosage increases the risk of undesirable BCG complications.
Administering the vaccine too deep increases the risk of discharging ulcer, lymphadenitis and abscess formation.

Treatment of complications after vaccination with BCG Vaccine AJV page6image193531008

Question 91

Phenoxymethylpenicillin 250 mg/5ml Powder for Oral Solution

Summary of Product Characteristics Updated 29-Apr-2022 | Flamingo Pharma (UK) Ltd

1. Name of the medicinal product
2. Qualitative and quantitative composition
3. Pharmaceutical form
4. Clinical particulars
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Fertility, pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. Pharmacological properties
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. Pharmaceutical particulars
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text

1. Name of the medicinal product

Phenoxymethylpenicillin 250mg/5ml Powder for Oral Solution

2. Qualitative and quantitative composition

Each 5ml of Oral Solution contains 250mg of Phenoxymethylpenicillin as Phenoxymethylpenicillin Potassium.

Excipient(s) with known effect:

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder for oral solution

White to off white granular powder, free from agglomerates or caking.

4. Clinical particulars

4.1 Therapeutic indications

Phenoxymethylpenicillin and phenoxymethylpenicillin potassium are indicated in the treatment of mild to moderately severe infections associated with micro-organisms whose susceptibility to penicillin is within the range of serum levels attained with the dosage form.

Phenoxymethylpenicillin is indicated for the treatment of the following infections (see section 4.4 and 5.1)

Streptococcal infections:

Pharyngitis

Scarlet fever

Skin and soft tissue infections (e.g. erysipelas)

Pneumococcal infections:

Pneumonia

Otitis media

Vincent’s gingivitis and pharyngitis

Phenoxymethylpenicillin is also indicated for (see section 5.1):

Prophylaxis of rheumatic fever and/or chorea

Prophylaxis of pneumococcal infection (e.g. in asplenia and inpatients with sickle cell disease

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Posology

For oral administration only.

The dosage and frequency of Phenoxymethylpenicillin depends on the severity and localisation of the infection and expected pathogens.

Phenoxymethylpenicillin Solution should be taken at least 30 minutes before or 2 hours after food, as ingestion of Phenoxymethylpenicillin with meals slightly reduces the absorption of the drug.

Phenoxymethylpenicillin 250mg is approximately equivalent to 400,000 units.

The usual dosage recommendations are as follows:

Adults (including the elderly) and children over 12 years:	250mg – 500mg every six hours
Children:
Infants (up to 1 year)	62.5mg every six hours
1-5 years	125mg every six hours
6-12 years	250mg every six hours

Prophylactic Use

Prophylaxis of rheumatic fever/chorea: 250mg twice daily on a continuing basis

Prophylaxis of pneumococcal infection (e.g. in asplenia and in sickle cell disease):

Adults and children over 12 years: 500mg every 12 hours

Children 6-12 years: 250mg every 12 hours

Children below 5 years: 125mg every 12 hours.

Elderly

The dosage is as for adults. The dosage should be reduced if renal function is markedly impaired.

Renal impairment

The dosage should be reduced if renal function is markedly impaired.

Hepatic impairment

Dosage adjustment may be necessary in patients with impaired liver function when they also have renal failure. In this situation the liver may be a major excretion route.

Method of Administration

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Phenoxymethylpenicillin is contraindicated in patients known to be hypersensitive to Penicillin or to any of the excipients listed in section 6.1 and should be used with caution in patients with known histories of allergy.

4.4 Special warnings and precautions for use

Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma. All degrees of hypersensitivity, including fatal anaphylaxis, have been observed with oral penicillin. These reactions are more likely to occur in individuals with a history of sensitivity to penicillins, cephalosporins and other allergens. Enquiries should be made for such a history before therapy is begun. If any allergic reaction occurs, the drug should be discontinued and the patient treated with the usual agents (e.g. adrenaline and other pressor amines, antihistamines and corticosteroids).

Oral therapy should not be relied upon for patients with severe illness, or with nausea, vomiting, gastric dilation, achalasia or intestinal hypermotility.

Occasionally patients do not absorb therapeutic amounts of orally administered penicillin.

Administer with caution in the presence of markedly impaired renal function, as safe dosage may be lower than the usually recommended doses.

Streptococcal infections should be treated for a minimum of 10 days, and post therapy cultures should be performed to confirm the eradication of the organisms.

Prolonged use of antibiotics may promote the over growth of non-susceptible organisms, including fungi. If super infection occurs, appropriate measures should be taken.

Sucrose:

This product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Aminoglycosides: Neomycin is reported to reduce the absorption of phenoxymethylpenicillin.

Anticoagulants: Penicillins may interfere with anticoagulant control.

Bacteriostatic antibiotics: Certain bacteriostatic antibiotics such as Chloramphenicol, Erythromycin and Tetracyclines have been reported to antagonise the bactericidal activity of penicillins and concomitant use is not recommended.

Guar gum: Reduced absorption of phenoxymethylpenicillin

Methotrexate: Use of Phenoxymethylpenicillin while taking methotrexate can cause reduced excretion of methotrexate thereby increasing the risk of toxicity.

Probenecid: Reduced excretion of phenoxymethylpenicillin by competing with it for renal tubular secretion.

Sulfinpyrazone: Excretion of penicillins reduced by sulfinpyrazone.

Typhoid vaccine (oral): Penicillins may inactivate oral typhoid vaccine if ingested concomitantly.

4.6 Fertility, pregnancy and lactation

Pregnancy:

There are no or a limited amount of data from the use of Phenoxymethylpenicillin in pregnant women. As a precautionary measure, it is preferable to avoid the use of Phenoxymethylpenicillin during pregnancy.

Breast-feeding:

Phenoxymethylpenicillin metabolites are excreted in human milk to such an extent that effects on breastfed newborns are likely.

4.7 Effects on ability to drive and use machines

None known

4.8 Undesirable effects

The most common reactions to oral penicillin are gastrointestinal effects and hypersensitivity reactions. Although hypersensitivity reactions have been reported much less frequently after oral than after parenteral therapy, it should be remembered that all forms of hypersensitivity, including fatal anaphylaxis have been observed with oral penicillin.

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 the yellow card scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms: A large oral overdose of penicillin may cause nausea, vomiting, stomach pain, diarrhoea, and rarely, major motor seizures. If other symptoms are present, consider the possibility of an allergic reaction. Hyperkalaemia may result from overdosage, particularly for patients with renal insufficiency.

Management: No specific antidote is known. Symptomatic and supportive therapy is recommended. Activated charcoal with a cathartic, such as sorbitol may hasten drug elimination. Penicillin may be removed by haemodialysis.

5. Pharmacological properties

5.1 Pharmacodynamic properties

General properties

ATC classification Pharmacotherapeutic Group: Beta lactamase sensitive natural penicillins ATC Code: J01C E02.

Mechanism of Action

Phenoxymethylpenicillin acts through interference with the final stage of synthesis of the bacterial cell wall. The action depends on its ability to bind certain membrane-bound proteins, (penicillin-binding proteins or PBPs) that are located beneath the cell wall. These proteins are involved in maintaining cell wall structure, in cell wall synthesis and in cell division, and appear to possess transpeptidase and carboxypeptidase activity.

PK/PD relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for phenoxymethylpenicillin.

Mechanism(s) of Resistance:

Phenoxymethylpenicillin is inhibited by penicillinase and other betalactamases that are produced by certain micro-organisms. The incidence of beta-lactamase producing organisms is increasing.

Mechanisms of resistance

The two main mechanisms of resistance to phenoxymethylpenicillin are:

• Inactivation by bacterial penicillinases and other beta-lactamases

• Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance.

EUCAST clinical MIC breakpoints to separate susceptible (S) pathogens from resistant (R) pathogens (version 1.0 22.11.210) are:

The susceptibility of streptococci Groups A, C and G and S. pneumoniae to phenoxymethylpenicillin is inferred from the susceptibility to benzylpenicillin.

EUCAST Species-related breakpoints (Susceptible≤/Resistant>) Units:
mg/L
Staphylococcus	≤0.12/>0.12
Streptococcus A, C, G	≤0.25/>0.25
S. pneumoniae	≤ 0.06/>2

Staphylococci: Most staphylococci are penicillinase-producers. Penicillinase producing strains are resistant. The benzylpenicillin breakpoint (shown) will mostly, but not unequivocally, separate beta-lactamase producers from nonproducers.

Streptococcus pneumoniae: For phenoxymethylpenicillin, report S. pneumoniae with benzylpenicillin MICs above 0.06 mg/L resistant.

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. Expert advice should be sought as necessary when the local prevalence of resistance is such that the utility of the agent in at least some types of infection is questionable.

Commonly susceptible species

Streptococcus A, B, C, G

Species for which acquired resistance may be a problem

Staphylococcus aureus

Streptococcus pneumonia

Staphylococcus epidermidis

5.2 Pharmacokinetic properties

Absorption

Rapidly but incompletely absorbed after oral administration (about 60% of an oral dose is absorbed). Calcium and potassium salts are better absorbed than the free acid. Absorption appears to be reduced in patients with coeliac disease. Absorption appears to be more rapid in fasting than non-fasting subjects.

Blood concentration: after an oral dose of 125mg, peak serum concentrations of 200 to 700ng/ml are attained in 2 hours. After an oral dose of 500mg, peak serum concentrations reach 3 to 5micrograms/ml in 30 to 60 minutes.

Half-life: Biological half-life is about 30 minutes, increased to about 4 hours in severe renal impairment.

Distribution

Widely distributed throughout the body and enters pleural and ascitic fluids and also in cerebrospinal fluid when the meninges are inflamed; Phenoxymethylpenicillin crosses the placenta and is secreted in the milk; (protein binding 50 to 80% bound plasma proteins).

Biotransformation: It is metabolised in the liver; several metabolites have been identified, including penicilloic acid.

Elimination: Unchanged drug and metabolites are excreted rapidly in the urine. (20% to 35% of an oral dose is excreted in the urine in 24 hours).

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of this SPC.

6. Pharmaceutical particulars

6.1 List of excipients

Sucrose

Saccharin Sodium (E954)

Flavour Orange powder (0473075)

Flavour Refreshing powder (0479539) (Menthol)

6.2 Incompatibilities

None known

6.3 Shelf life

24 Months Unopened, 7 days after reconstitution

6.4 Special precautions for storage

Dry powder: Store below 25°C, Store in the original package.

Reconstituted solution: Store up to 7 days at 2°C – 8°C in a refrigerator.

6.5 Nature and contents of container

Translucent HDPE round bottle with White Round polypropylene CR Cap liner containing 100 ml of oral Solution on reconstitution.

6.6 Special precautions for disposal and other handling

Phenoxymethylpenicillin is Slight opaque solution with orange odour. Add 65mls of potable water for the 250mg/5ml strength of product and shake gently until all powder is dissolved.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Flamingo Pharma UK Ltd.

I^st floor, Kirkland House,

11-15 Peterborough Road,

Harrow, Middlesex,

HA12AX, United Kingdom.

8. Marketing authorisation number(s)

PL 43461/0028

9. Date of first authorisation/renewal of the authorisation

27/09/2019

10. Date of revision of the text

21/10/2020

Company Contact Details

Flamingo Pharma (UK) Ltd

Question 94

Dental Practitioners’ Formulary

Navigate to section

List of Dental Preparations
Details of DPF preparations

List of Dental Preparations

The following list has been approved by the appropriate Secretaries of State, and the preparations therein may be prescribed by dental practitioners on form FP10D (GP14 in Scotland, WP10D in Wales).

Licensed sugar-free versions, where available, are preferred.

Licensed alcohol-free mouthwashes, where available, are preferred.

Aciclovir Cream, BP
Aciclovir Oral Suspension, BP, 200 mg/5 mL
Aciclovir Tablets, BP, 200 mg
Aciclovir Tablets, BP, 800 mg
Amoxicillin Capsules, BP
Amoxicillin Oral Powder, DPF
Amoxicillin Oral Suspension, BP
Artificial Saliva Gel, DPF
Artificial Saliva Oral Spray, DPF
Artificial Saliva Pastilles, DPF
Artificial Saliva Protective Spray, DPF
Artificial Saliva Substitutes as listed below (to be prescribed only for indications approved by ACBS (patients suffering from dry mouth as a result of having or, having undergone, radiotherapy or sicca syndrome):
- BioXtra® Gel Mouthspray
- BioXtra® Moisturising Gel
- Glandosane®
- Saliveze®
Artificial Saliva Substitute Spray, DPF
Aspirin Tablets, Dispersible, BP
Azithromycin Capsules, 250 mg, DPF
Azithromycin Oral Suspension, 200 mg/5 mL, DPF
Azithromycin Tablets, 250 mg, DPF
Azithromycin Tablets, 500 mg, DPF
Beclometasone Pressurised Inhalation, BP, 50 micrograms/ metered inhalation, CFC-free, as:
- Clenil Modulite®
Benzydamine Mouthwash, BP 0.15%
Benzydamine Oromucosal Spray, BP 0.15%
Betamethasone Soluble Tablets, 500 micrograms, DPF
Carbamazepine Tablets, BP
Cefalexin Capsules, BP
Cefalexin Oral Suspension, BP
Cefalexin Tablets, BP
Cefradine Capsules, BP
Cetirizine Oral Solution, BP, 5 mg/5 mL
Cetirizine Tablets, BP, 10 mg
Chlorhexidine Gluconate Gel, BP
Chlorhexidine Mouthwash, BP
Chlorhexidine Oral Spray, DPF
Chlorphenamine Oral Solution, BP
Chlorphenamine Tablets, BP
Choline Salicylate Dental Gel, BP
Clarithromycin Oral Suspension, 125 mg/5 mL, DPF
Clarithromycin Oral Suspension, 250 mg/5 mL, DPF
Clarithromycin Tablets, BP
Clindamycin Capsules, BP
Co-amoxiclav Tablets, BP, 250/125 (amoxicillin 250 mg as trihydrate, clavulanic acid 125 mg as potassium salt)
Co-amoxiclav Oral Suspension, BP, 125/31 (amoxicillin 125 mg as trihydrate, clavulanic acid 31.25 mg as potassium salt)/5 mL
Co-amoxiclav Oral Suspension, BP, 250/62 (amoxicillin 250 mg as trihydrate, clavulanic acid 62.5 mg as potassium salt)/5 mL
Diazepam Oral Solution, BP, 2 mg/5 mL
Diazepam Tablets, BP
Diclofenac Sodium Tablets, Gastro-resistant, BP
Dihydrocodeine Tablets, BP, 30 mg
Doxycycline Tablets, Dispersible, BP
Doxycycline Capsules, BP, 100 mg
Doxycycline Tablets, 20 mg, DPF
Ephedrine Nasal Drops, BP
Erythromycin Ethyl Succinate Oral Suspension, BP
Erythromycin Ethyl Succinate Tablets, BP
Erythromycin Stearate Tablets, BP
Erythromycin Tablets, Gastro-resistant, BP
Fluconazole Capsules, 50 mg, DPF
Fluconazole Oral Suspension, 50 mg/5 mL, DPF
Hydrocortisone Cream, BP, 1%
Hydrocortisone Oromucosal Tablets, BP
Hydrogen Peroxide Mouthwash, BP, 6%
Ibuprofen Oral Suspension, BP, sugar-free
Ibuprofen Tablets, BP
Lansoprazole Capsules, Gastro-resistant, BP
Lidocaine Ointment, BP, 5%
Lidocaine Spray 10%, DPF
Loratadine Syrup, 5 mg/5 mL, DPF
Loratadine Tablets, BP, 10 mg
Menthol and Eucalyptus Inhalation, BP 1980
Metronidazole Oral Suspension, BP
Metronidazole Tablets, BP
Miconazole Cream, BP
Miconazole Oromucosal Gel, BP
Miconazole and Hydrocortisone Cream, BP
Miconazole and Hydrocortisone Ointment, BP
Nystatin Oral Suspension, BP
Omeprazole Capsules, Gastro-resistant, BP
Oxytetracycline Tablets, BP
Paracetamol Oral Suspension, BP
Paracetamol Tablets, BP
Paracetamol Tablets, Soluble, BP
Phenoxymethylpenicillin Oral Solution, BP
Phenoxymethylpenicillin Tablets, BP
Promethazine Hydrochloride Tablets, BP
Promethazine Oral Solution, BP
Saliva Stimulating Tablets, DPF
Sodium Chloride Mouthwash, Compound, BP
Sodium Fluoride Mouthwash, BP
Sodium Fluoride Oral Drops, BP
Sodium Fluoride Tablets, BP
Sodium Fluoride Toothpaste 0.619%, DPF
Sodium Fluoride Toothpaste 1.1%, DPF
Sodium Fusidate Ointment, BP
Temazepam Oral Solution, BP
Temazepam Tablets, BP
Tetracycline Tablets, BP

Preparations in this list which are not included in the BP or BPC are described under Details of DPF preparations.

For details of preparations that can be prescribed, see individual entries under the relevant drug monographs throughout the BNF publications.

Details of DPF preparations

Preparations on the List of Dental Preparations which are specified as DPF are described as follows in the DPF.

Although brand names have sometimes been included for identification purposes preparations on the list should be prescribed by non-proprietary name.

Amoxicillin Oral Powder

amoxicillin (as trihydrate) 3 g sachet

Artificial Saliva Gel

consists of lactoperoxidase, lactoferrin, lysozyme, glucose oxidase, xylitol in a gel basis

Artificial Saliva Oral Spray

(proprietary product: Xerotin) consists of water, sorbitol, carmellose (carboxymethylcellulose), potassium chloride, sodium chloride, potassium phosphate, magnesium chloride, calcium chloride and other ingredients, pH neutral

Artificial Saliva Pastilles

(proprietary product: Salivix), consists of acacia, malic acid, and other ingredients

Artificial Saliva Protective Spray

(proprietary product: Aequasyal) consists of oxidised glycerol triesters, silicon dioxide, flavouring agents, aspartame

Artificial Saliva Substitute Spray

(proprietary product: AS Saliva Orthana Spray) consists of mucin, methylparaben, benzalkonium chloride, EDTA, xylitol, peppermint oil, spearmint oil, mineral salts

Azithromycin Capsules

azithromycin 250 mg

Azithromycin Oral Suspension 200 mg/5 mL

azithromycin 200 mg/5 mL when reconstituted with water

Azithromycin Tablets

azithromycin 250 mg and 500 mg

Betamethasone Soluble Tablets 500 micrograms

betamethasone (as sodium phosphate) 500 micrograms

Chlorhexidine Oral Spray

(proprietary product: Corsodyl Oral Spray), chlorhexidine gluconate 0.2%

Clarithromycin Oral Suspension 125 mg/5 mL

clarithromycin 125 mg/5 mL when reconstituted with water

Clarithromycin Oral Suspension 250 mg/5 mL

clarithromycin 250 mg/5 mL when reconstituted with water

Doxycycline Tablets 20 mg

(proprietary product: Periostat), doxycycline (as hyclate) 20 mg

Fluconazole Capsules 50 mg

fluconazole 50 mg

Fluconazole Oral Suspension 50 mg/5 mL

(proprietary product: Diflucan), fluconazole 50 mg/ 5 mL when reconstituted with water

Lidocaine Spray 10%

(proprietary product: Xylocaine Spray), lidocaine 10% supplying 10 mg lidocaine/spray

Loratadine Syrup 5 mg/5 mL

loratadine 5 mg/5 mL

Saliva Stimulating Tablets

(proprietary product: SST), citric acid, malic acid and other ingredients in a sorbitol base

Sodium Fluoride Toothpaste 0.619%

(proprietary product: Duraphat ‘2800 ppm’ Toothpaste), sodium fluoride 0.619%

Sodium Fluoride Toothpaste 1.1%

(proprietary product: Duraphat ‘5000 ppm’ Toothpaste), sodium fluoride 1.1%

-END OF RESOURCES-

The Lancashire Clinical Mock Exam 2023 Paper2

Tohidul March 13, 2023

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