Hiramicin

Overdose

Acute overdosage with antibiotics is rare. In the event of overdosage discontinue medication. Gastric lavage plus appropriate supportive treatment is indicated.

Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

Acute overdosage with antibiotics is rare. In the event of overdosage discontinue medication. Gastric lavage plus appropriate supportive treatment is indicated.

Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

To date no significant acute toxicity has been described in the case of a single oral intake of a multiple of therapeutic doses of doxycycline. In case of overdosage there is, however, a risk of parenchymatous hepatic and renal damage and of pancreatitis.

The usual dose of Hiramicin is low when compared with the usual doses for doxycycline when used for antimicrobial therapy. Therefore clinicians should bear in mind that a significant proportion of overdoses are likely to produce blood concentrations of doxycycline within the therapeutic range of antimicrobial treatment, for which there is a large quantity of data supporting the safety of the drug. In these cases observation is recommended. In cases of significant overdosage, doxycycline therapy should be stopped immediately; and symptomatic measures undertaken as required. Intestinal absorption of unabsorbed doxycycline should be minimised by producing non-absorbable chelate complexes by the administration of magnesium or calcium salt containing antacids. Gastric lavage should be considered.

Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

Incompatibilities

Not applicable.

None known

Not applicable.

Undesirable effects

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

* 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.

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.

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

Adverse Reactions Table

* Symptoms included blurring of vision, scotomata and diplopia. Permanent visual loss has been reported.

Tetracyclines may cause discolouration of teeth and enamel hypoplasia, but usually only after long-term use.

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.

The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Due to oral doxycycline’s virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines:

Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed.

Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above.

Renal: Rise in BUN has been reported and is apparently dose-related.

Hypersensitivity reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus.

Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.

Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline

Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur.

The most commonly reported adverse reactions in Phase III trials were headache (26%) and common cold (22%). The following table lists those adverse reactions occurring in four Phase III trials conducted in 213 patients.

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

Gastrointestinal: Anorexia, nausea, vomiting, diarrhoea, glossitis, dysphagia, enterocolitis and inflammatory lesions with monilial overgrowth in the anogenital region. Hepatotoxity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Oesophagitis and oesophageal ulceration have been reported, most often in patients administered the hyclate salt in capsule form. Most of these patients took medication just prior to going to bed.

Skin: Maculo papular, erythematous rashes and Stevens-Johnson syndrome. Skin photosensitivity can occur. Exfoliative dermatitis has been reported but is uncommon.

Renal: An apparently dose related increase in blood urea has been reported with tetracyclines.

Blood: Thrombocytopenia, neutropenia, haemolytic anaemia, eosinophilia and porphyria have been reported with tetracyclines.

Hypersensitivity reactions: Exacerbation of systemic lupus erythematosus, anaphylaxis, anaphylactoid purpura, pericarditis, urticaria and angioneurotic oedema.

Musculoskeletal: Arthralgia

Other: Bulging fontanelles in infants and benign intracranial hypertension in adults has been reported with the use of tetracyclines. Treatment should cease if evidence of raised intracranial pressure develops. These conditions disappeared rapidly when the drug was discontinued. Brown-black microscopic discolouration of thyroid tissue has been reported with long-term use of tetracyclines. Thyroid function is normal.

Adverse reactions typical of the tetracycline class of drugs are less likely to occur during medication with Hiramicin, due to the reduced dosage and the relatively low serum levels involved. This assertion is supported by several clinical trials which suggest that no significant differences exist with regard to frequency of adverse events between active and placebo groupings. However, the clinician should always be aware of the possibility of adverse events occurring and should monitor patients accordingly.

The following adverse events have been reported during post-marketing:

(Frequency estimate: very common > 1 in 10; common >1 in 100 to <1 in 10; uncommon >1 in 1000 to <1 in 100; rare >1 in 10,000 to <1 in 1000; very rare <1 in 10,000) and not known : cannot be estimated from the available data

Infections

Rare: Vaginal moniliasis, Anogenital moniliasis

Immune system disorders

Rare: Mild allergic reactions

Not known: Jarisch-Herxheimer reaction

Nervous system disorders

Rare: Headache

Very rare: Dizziness

Gastrointestinal disorders

Rare: Nausea, diarrhoea, dyspepsia

Very rare: Abdominal pain, constipation, dry mouth, superficial tooth discolouration

There have been isolated case reports of bloody diarrhoea, colitis and pseudomembranous colitis.

Skin and subcutaneous tissue disorders

Rare: Rash

Very rare: Urticaria, pruritus, skin photosensitivity.

Unknown: Photo-onycholysis.

Musculoskeletal disorders

Very rare: Arthralgia

General disorders

Very rare: Asthenia

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. Tel: Freephone 0808 100 3352. Website: www.mhra.gov.uk/yellowcard.

Preclinical safety data

None stated

Not applicable.

The carcinogenic potential of doxycycline has been investigated and no changes indicative of a direct carcinogenic effect were seen. Increases in benign tumours of the mammary gland (fibroadenoma), uterus (polyp) and thyroid (C-cell adenoma), which are consistent with a hormonal effect, were observed in treated females. Doxycycline has shown no mutagenic activity and no convincing evidence of clastogenic activity.

Effects on fertility and reproductive performance and on pre- and post-natal toxicity have been assessed in rats over the dose range 50 to 500 mg/kg/day. At 50 mg/kg/day (88 times the human dose) there was a decrease in the straight-line velocity of sperm, but there was no apparent effect on male or female fertility or on sperm morphology. Maternal toxicity at 500 mg/kg/day was shown by noisy breathing, loose faeces, and transient reductions in both body weight gain and food consumption after parturition with a slight increase in the duration of gestation. No maternal toxicity was apparent at or below 100 mg/kg/day and there was no effect on the F1 generation at 50 mg/kg/day during parturition, lactation or post-weaning. Developmental toxicity studies have not been conducted, but doxycycline is known to cross the placenta.

Hyperpigmentation of the thyroid following administration of members of the tetracycline class has been observed in rats, minipigs, dogs and monkeys and thyroid hyperplasia has occurred in rats, dogs, chickens and mice.

The anticipated human dose for doxycycline, 20 mg b.i.d. is equivalent to ~0.5 mg/kg/day for a 70 kg man. At this dose plasma Cmax and AUC0-24 were 780 ng/ml and 10954 ng*h/ml respectively.

Toxicity following repeated oral administration has been evaluated in rats and cynomolgus monkeys. Discolouration of the thyroid was a finding common to rats exposed at 25 mg/kg/day for 13 weeks or 20 mg/kg/day for 26 weeks, and to cynomolgus monkeys at 30 mg/kg/day for 1 year. Cmax and AUC0-24 following a single oral dose of 25 mg/kg were 2.2 and 1.6 times respectively the values recorded in man. Dose-related increases in both the incidence and severity of tubular degeneration/regeneration in the kidney were seen following administration to cynomolgus monkeys for 28 days or 52 weeks. At 5 mg/kg/day, focal lesions were present after 28 days, but no lesions were present in monkeys treated for 52 weeks. Mean plasma Cmax and AUC0-24 values at 28 days in monkeys receiving 5 mg/kg/day were 1235 ng/ml and 11600 ng*h/ml respectively and there was no evidence of accumulation.

In humans the use of tetracyclines during tooth development may cause permanent discolouration of the teeth (yellow-grey-brown). This reaction is more common during long-term use of the drug but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. As for other tetracyclines, doxycycline forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Tetracyclines, ATC code: J01 AA02.

Hiramicin is primarily bacteriostatic and is believed to exert its antimicrobial effect by the inhibition of protein synthesis. Hiramicin is active against a wide range of Gram-positive and Gram-negative bacteria and certain other micro-organisms.

Pharmacotherapeutic group: Tetracyclines, ATC code: J01 AA02

Hiramicin is primarily bacteriostatic and is believed to exert its antimicrobial effect by the inhibition of protein synthesis. Hiramicin is active against a wide range of Gram-positive and Gram-negative bacteria and certain other micro-organisms.

Pharmacotherapeutic group: Tetracyclines

ATC code: J01A A02

The active ingredient of Hiramicin, doxycycline, is synthetically derived from oxytetracycline, with a molecular formula of C22H24N2O8-HCl-½ C2H5OH-½ H2O.

Hiramicin is an inhibitor of collagenase activity. Studies have shown that at the proposed 20 mg b.i.d. dose level, Hiramicin reduces the elevated collagenase activity in the gingival crevicular fluid of patients with chronic adult periodontitis, whilst not demonstrating any clinical evidence of anti-microbial activity.

Susceptibility

The dosage achieved with this product during administration is well below the concentration required to inhibit microorganisms commonly associated with adult periodontitis. Clinical studies with this product demonstrated no effect on total anaerobic and facultative bacteria in plaque samples from patients administered this dose regimen for 9 to 18 months. This product SHOULD NOT be used for reducing the numbers of, or eliminating, those microorganisms associated with periodontitis.

Pharmacokinetic properties

Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and faeces at high concentrations and in a biologically active form. Doxycycline is virtually completely absorbed after oral administration. Studies reported to date indicate that the absorption of doxycycline, unlike certain other tetracyclines, is not notably influenced by the ingestion of food or milk. Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 micrograms/ml of doxycycline at 2 hours decreasing to 1.45 micrograms/ml at 24 hours. Doxycycline has a high degree of lipid solubility and a low affinity for calcium. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.

Absorption

Tetracyclines are readily absorbed and are bound to proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and faeces at high concentration and in a biologically active form. Hiramicin is virtually completely absorbed after oral administration. Studies reported to date indicate that the absorption of Hiramicin unlike certain other tetracyclines, is not notably influenced by the ingestion of food or milk.

Following a 200mg dose, normal adult volunteers averaged peak serum levels of 2.6 micrograms/ml at 2hours decreasing to 1.45micrograms/ml at 24 hours. Hiramicin has a high degree of lipid solubility and a low affinity for calcium. It is highly stable in normal human serum. Hiramicin will not degrade into an epianhydro form.

Following administration of a single dose of Hiramicin MPC under fasting conditions, the AUCinf and Cmax were 26.7 mcg-h/mL and 1.6 mcg/mL, respectively. The Tmax was 2.8 hours. In a single-dose study to evaluate the relative bioavailability in healthy adult subjects under fasted conditions, Hiramicin MPC 120 mg Tablets were found to be bioequivalent to Hiramicin 100 mg Tablets. When a single dose of Hiramicin MPC 120 mg Tablet was administered with a standardized high-fat high-calorie meal, (937kcal consisting of approximately 55% fat, 30% carbohydrate and 15% protein), the Cmax was approximately 30% lower, but there was no significant difference in the AUCinf compared to administration under fasting conditions.

Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min.

Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life.

Absorption:

Doxycycline is almost completely absorbed after oral administration. Following ingestion of 20 mg doxycycline twice daily, mean maximum plasma concentrations were 0.79 µg/ml. Peak levels were generally achieved 2 hours after administration. Food intake reduced the extent of absorption by 10% and decreased and delayed the peak plasma levels.

Distribution:

Doxycycline is greater than 90% bound to plasma proteins and has an apparent volume of distribution of 50L.

Metabolism:

Major metabolic pathways of doxycycline have not been identified, however, enzyme inducers decrease the half-life of doxycycline.

Elimination:

Doxycycline is excreted in the urine and faeces as unchanged drug. Between 40% and 60% of an administered dose can be accounted for in the urine by 92 hours, and approximately 30% in the faeces. The terminal half-life after a single 20 mg doxycycline dose averaged 18h.

Special populations:

The half-life is not significantly altered in patients with severely impaired renal function. Doxycycline is not eliminated to any great extent during haemodialysis.

Special warnings and precautions for use

Use in children The use of drugs of the tetracycline class during tooth development (pregnancy, infancy and childhood to the age of 12 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 of doxycycline is contraindicated in pediatric patients under the age of 12 years..

Use in patients with impaired hepatic function Hiramicin 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 Hiramicin 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. 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. 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.

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)..

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.

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.

Use in patients with impaired hepatic function

Hiramicin should be administered with caution in patients with hepatic impairment or those receiving potentially hepatotoxic drugs. Abnormal hepatic function has been reported rarely and has been caused by both oral and parenteral administration of tetracyclines including Hiramicin.

Use in patients with renal impairment

Excretion of Hiramicin by the kidney is about 40%/72 hours in patients 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 Hiramicin in individuals with normal and severely impaired renal function. Haemodialysis does not alter the serum half-life of Hiramicin. 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 Hiramicin in patients with impaired renal function.

Photosensitivity

Photosensitivity manifested by exaggerated sunburn reaction has been observed in some individuals taking tetracyclines, including Hiramicin. 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 sign of skin erythema.

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 Hiramicin. 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 Hiramicin. If visual disturbances occur 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 Hiramicin should be avoided because isotretinoin is also known to cause benign intracranial hypertension (pseudotumor cerebri)..

Microbial overgrowth

The use of antibiotics may occasionally result in over-growth 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 Hiramicin, 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 the antibacterial agents.

Clostridium difficile

Associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including Hiramicin, 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 the capsule and tablet form of the drugs in the tetracycline class, including Hiramicin. Most of the 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 when 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 ten days.

Myasthenia gravis

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

Systemic lupus erythematosus

Tetracyclines can cause the exacerbation of SLE.

Methoxyflurane

Caution is advised in administering tetracyclines with methoxyflurane.

Included as part of the "PRECAUTIONS" Section

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 discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use Hiramicin MPC in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Hiramicin MPC Tablets, and may range in severity from mild diarrhea 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 diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt 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.

Hiramicin MPC may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue use and institute appropriate therapy.

Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including Hiramicin MPC. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Avoid concomitant use of isotretinoin and Hiramicin MPC because isotretinoin is also known to cause pseudotumor cerebri.

Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. 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.

All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued..

The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.

Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains.

Doxycycline does not suppress P. falciparum’s sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas.

Prescribing Hiramicin MPC in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed.

Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been ev idence of oncogenic activity in rats in studies with the related antibiotics, oxytetracycline (adrenal and pituitary tumors) a nd minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterials (tetracycline, oxytetracycline).

Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied.

There are no adequate studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS -the Teratogen Information System -concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk.1 In the U.S. general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively [see Data].

Embryo/Fetal Risk

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus..

Human Data

A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases.2

A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age.3

Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not contraindicated. The effects of prolonged exposure to doxycycline on breast milk production and breast fed neonates, infants and children are unknown.4 The developmental and health benefits of breast feeding should be considered along with the mother’s clinical need for Hiramicin MPC and any potential adverse effects on the breast fed child from Hiramicin MPC or from the underlying maternal condition.

Because of the effects of drugs of the tetracycline-class on tooth development and growth, use Hiramicin MPC in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies.

Clinical studies of Hiramicin MPC did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Hiramicin MPC Tablets each contain less than 10 mg of sodium.

REFERENCES

1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195. The TERIS (Teratogen Information System) is available at: http://www.micromedexsolutions.com/ (cited: 2016 Jan).

2. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528.

3. Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315-317.

4. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); [Last Revision Date 2015 March 10; cited 2016 Jan]. Doxycycline; LactMed Record Number: 100; [about 3 screens]. Available from: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

Hiramicin is indicated for treatment periods of 3 months. Hiramicin should not be administered for more than 3 consecutive three month periods.

No dosage modification is necessary in elderly patients.

Renal Impairment:

No dosage adjustment is necessary in the presence of renal impairment.

Children:

For use in children, see 'Contraindications'.

In common with other drugs of the tetracycline class, Hiramicin is contra-indicated in infants and children up to 12 years of age.

Doxycycline should not be administered to patients who have shown hypersensitivity to doxycycline hyclate, other tetracyclines or to any of the excipients.

Patients known to have, or suspected to have, achlorhydria should not be prescribed doxycycline.

Use of doxycycline is contra-indicated during pregnancy and lactation (See 4.6 Pregnancy and lactation).

Tablet forms of the tetracycline class of drugs may cause oesophageal irritation and ulceration. To avoid oesophageal irritation and ulceration, adequate fluids should be taken with this medication. Hiramicin should be swallowed whilst in an upright sitting or standing posture. Tablets taken in the evening should be taken well in advance of retiring (see 4.2: Posology and Method of Administration).

Whilst no overgrowth by opportunistic microorganisms such as yeast were noted during clinical studies, Hiramicin therapy may result in overgrowth of non-susceptible microorganisms including fungi (with clinical symptoms of persistent bad breath, reddening of the gums, etc.). Periodic observation of the patient is essential. Hiramicin therapy has been associated with diarrhoea, colitis and vaginal moniliasis which may suggest overgrowth of non-susceptible micro-organisms. If overgrowth by resistant organisms appears, Hiramicin therapy should be discontinued and an appropriate treatment instituted.

Hiramicin should be used with caution in patients with a history of or predisposition to oral candidosis. The safety and effectiveness of Hiramicin has not been established for the treatment of periodontitis in patients with coexistent oral candidosis. Whilst not observed during clinical trials with Hiramicin, the use of tetracyclines may increase the incidence of vaginal candidosis.

The blood doxycycline levels in patients treated with Hiramicin are lower than in those treated with conventional antimicrobial formulations of doxycycline. As, however, there are no data to support safety in hepatic impairment at this lower dose, Hiramicin should be administered with caution to patients with hepatic impairment or to those receiving potentially hepatotoxic drugs.

Caution should be observed in the treatment of patients with myasthenia gravis who may be at risk of worsening of the condition.

All patients receiving doxycycline including Hiramicin should be advised to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption etc.) occurs. Sunscreen or sunblock should be considered. Treatment should cease at the first sign of skin erythema.

In common with the use of antimicrobial drugs in general, there is a risk of the development of pseudomembranous colitis with doxycycline treatment. In the event of the development of diarrhoea during treatment with Hiramicin, the possibility of pseudomembranous colitis should be considered and appropriate therapy instituted. This may include the discontinuation of doxycycline and the institution of specific antibiotic therapy (e.g vancomycin). Agents inhibiting peristalsis should not be employed in this situation.

In the event of a severe acute hypersensitivity reaction (e.g. anaphylaxis), treatment with Hiramicin must be stopped at once and the usual emergency measures taken (e.g. administration of antihistamines, corticosteroids, sympathomimetics and if necessary artificial respiration instituted).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Effects on ability to drive and use machines

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

Hiramicin therapy has been associated with nausea and dizziness. Those affected should not drive or operate machinery.

Special precautions for disposal and other handling

No special requirements.