VIBRAMYCIN-D Dispersible Tablet Ref.[6808] Active ingredients: Doxycycline

Paediatric population

The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discolouration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use doxycycline in paediatric patients aged younger than 8 years only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g. Rocky Mountain spotted fever), only when there are no adequate alternative therapies.

Although the risk of permanent teeth staining is rare in children aged 8 years to less than 12 years, the use of doxycycline should be carefully justified in situations where other drugs are not available, are not likely to be effective or are contraindicated.

Use in patients with impaired hepatic function

Vibramycin should be administered with caution to patients with hepatic impairment or those receiving potentially hepatotoxic drugs.

Abnormal hepatic function has been reported rarely and has been caused by both the oral and parenteral administration of tetracyclines, including doxycycline.

Use in patients with renal impairment

Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal renal function. This percentage excretion may fall to a range as low as 1-5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10ml/min). Studies have shown no significant difference in the serum half-life of doxycycline in individuals with normal and severely impaired renal function. Haemodialysis does not alter the serum half-life of doxycycline. The anti-anabolic action of the tetracyclines may cause an increase in blood urea. Studies to date indicate that this anti-anabolic effect does not occur with the use of Vibramycin in patients with impaired renal function.

Serious skin reactions

Serious skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline (see section 4.8). If serious skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.

Photosensitivity

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including doxycycline (see section 4.8). Patients likely to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs and treatment should be discontinued at the first evidence of skin erythema.

Photoonycholysis has also been reported in patients receiving doxycycline (see section 4.8).

Benign intracranial hypertension

Bulging fontanelles in infants have been reported in individuals receiving tetracyclines. Benign intracranial hypertension (pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline. Benign intracranial hypertension (pseudotumor cerebri) is usually transient, however cases of permanent visual loss secondary to benign intracranial hypertension (pseudotumor cerebri) have been reported with tetracyclines including doxycycline. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. Concomitant use of isotretinoin or other systemic retinoids and doxycycline should be avoided because isotretinoin is also known to cause benign intracranial hypertension (pseudotumor cerebri). (See section 4.5).

Microbiological overgrowth

The use of antibiotics may occasionally result in the overgrowth of non-susceptible organisms including Candida. If a resistant organism appears, the antibiotic should be discontinued and appropriate therapy instituted.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including doxycycline, and has ranged in severity from mild to life-threatening. It is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Oesophagitis Instances of oesophagitis and oesophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline class, including doxycycline. Most of these patients took medications immediately before going to bed or with inadequate amounts of fluid.

Porphyria

There have been rare reports of porphyria in patients receiving tetracyclines.

Venereal disease

When treating venereal disease, where co-existent syphilis is suspected, proper diagnostic procedures including dark-field examinations should be utilised. In all such cases monthly serological tests should be made for at least four months.

Beta-haemolytic streptococci infections

Infections due to group A beta-haemolytic streptococci should be treated for at least 10 days.

Myasthenia gravis

Due to a potential for weak neuromuscular blockade, care should be taken in administering tetracyclines to patients with myasthenia gravis.

Systemic lupus erythematosus

Tetracyclines can cause exacerbation of SLE.

Methoxyflurane

Caution is advised in administering tetracyclines with methoxyflurane. See section 4.5.

Jarisch-Herxheimer reaction

Some patients with spirochete infections may experience a Jarisch-Herxheimer reaction shortly after doxycycline treatment is started. Patients should be reassured that this is a usually self-limiting consequence of antibiotic treatment of spirochete infections.

The absorption of doxycycline may be impaired by concurrently administered antacids containing aluminium, calcium, magnesium or other drugs containing these cations; oral zinc, iron salts or bismuth preparations. Dosages should be maximally separated.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving Vibramycin in conjunction with penicillin.

There have been reports of prolonged prothrombin time in patients taking warfarin and doxycycline. Tetracyclines depress plasma prothrombin activity and reduced doses of concomitant anticoagulants may be necessary.

The serum half-life of doxycycline may be shortened when patients are concurrently receiving barbiturates, carbamazepine or phenytoin. An increase in the daily dosage of Vibramycin should be considered.

Alcohol may decrease the half-life of doxycycline.

A few cases of pregnancy or breakthrough bleeding have been attributed to the concurrent use of tetracycline antibiotics with oral contraceptives.

Doxycycline may increase the plasma concentration of ciclosporin. Co-administration should only be undertaken with appropriate monitoring.

The concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity. See section 4.4.

Concomitant use of isotretinoin or other systemic retinoids and doxycycline should be avoided. Each of these agents used alone has been associated with benign intracranial hypertension (pseudotumor cerebri). (See section 4.4).

Laboratory test interactions

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

See section 4.3.

The effect of doxycycline on the ability to drive or operate heavy machinery has not been studied. There is no evidence to suggest that doxycycline may affect these abilities.

The following adverse reactions have been observed in patients receiving tetracyclines, including doxycycline.

Common ≥1/100 to <1/10
Uncommon ≥1/1000 to <1/100
Rare ≥1/10,000 to <1/1000
Not known – Cannot be estimated from the available data

Infections and infestations

Uncommon: Vaginal infection

Rare: Candida Infection

Blood and lymphatic system disorders

Rare: Haemolytic anaemia, neutropenia, thrombocytopenia, eosinophilia

Immune system disorders

Common: Hypersensitivity (including anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, angioedema, exacerbation of systemic lupus erythematosus, pericarditis, serum sickness, Henoch-Schonlein purpura, hypotension, dyspnoea, tachycardia, peripheral oedema and urticaria)

Rare: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Jarisch-Herxheimer reaction^b (see section 4.4)

Endocrine disorders

Rare: Brown-black microscopic discolouration of thyroid glands

Metabolism and nutrition disorders

Rare: Porphyria, decreased appetite

Nervous system disorders

Common: Headache

Rare: Anxiety, benign intracranial hypertension (pseudotumor cerebri)*, fontanelle bulging

Ear and labyrinth disorders

Rare: Tinnitus

Vascular disorders

Rare: Flushing

Gastrointestinal disorders

Common: Nausea/vomiting

Uncommon: Dyspepsia (Heartburn/gastritis)

Rare: Pancreatitis, pseudomembranous colitis, Clostridium difficile colitis, oesophageal ulcer, oesophagitis, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, dysphagia, abdominal pain, diarrhoea, glossitis, stomatitis

Not known: Tooth discolouration^a

Hepatobiliary disorders

Rare: Hepatic failure, hepatitis, hepatotoxicity, jaundice, hepatic function abnormal

Skin and subcutaneous tissue disorders

Common: Photosensitivity reaction, rash including maculopapular and erythematous rashes

Rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, dermatitis exfoliative, photoonycholysis, skin hyperpigmentationc

Musculoskeletal, connective tissue and bone disorders

Rare: Arthralgia, myalgia

Renal and urinary disorders

Rare: Blood urea increased

^* Symptoms included blurring of vision, scotomata and diplopia. Permanent visual loss has been reported.
^a Reversible and superficial discolouration of permanent teeth has been reported with the use of doxycycline but frequency cannot be estimated from available data.
^b in the setting of spirochete infections treated with doxycycline.
^c with chronic use of doxycycline.

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.

Not applicable.