M Plus

Uses

M Plus is used for oral administration, for the treatment of infections caused by tetracycline sensitive organisms and some tetracycline resistant strains of staphylococci. Indications include: Acne, skin and soft tissue infections, ophthamological infections, acute and chronic bronchitis, bronchiectasis, lung abscess, ear, nose and throat infections, pelvic inflammatory disease, nocardiosis, urinary tract infections, gonorrhoea, non-gonococcal urethritis and prostatitis. M Plus may also be used in prophylactic treatment of asymptomatic meningococcal carriers. Also used for pre- and post-operative prophylaxis of infection.
Renal impairment: As adults even in cases of mild to moderate renal impairment. However, caution is advised in patients with severe renal impairment.
Paediatric population: M Plus is not recommended in children under 12 years. Children over 12 years: 50mg every 12 hours.

M Plus is also used to associated treatment for these conditions: Bartonellosis, Brucellosis, Campylobacter fetus, Chancroid, Cholera, Conjunctivitis, Inclusion, Granuloma Inguinale, Lymphogranuloma Venereum, Nongonococcal urethritis, Periodontitis, Plague, Psittacosis, Q Fever, Relapsing Fever, Respiratory Tract Infections (RTI), Rickettsia Infections, Rickettsialpox, Rocky Mountain Spotted Fever, Trachoma, Tularemia, Typhus Fever, Inflammatory lesions

How M Plus works

Tetracyclines enter bacterial cells through OmpF and OmpC porins by coordinating with cations like magnesium. This allows tetracyclines into the periplasm where they dissociate, allowing the lipophilic tetracycline to diffuse into the bacterial cytoplasm. Tetracyclines prevent aminoacyl-tRNA from binding to the 30S ribosome, inhibiting protein synthesis.

Dosage

M Plus dosage

• Routine antibiotic use: 200 mg daily in divided doses
• Acne: 50 mg twice daily for at least 6 weeks.
• Gonorrhoea: Males: 200 mg initially followed by 100 mg every 12 hours for a minimum of 4 days. Post therapy cultures within 2-3 days. Females: May require a more prolonged therapy.
• Prophylaxis of asymptomatic meningococcal carriers: 100 mg twice daily for 5 days, followed by treatment with rifampicin.

Side Effects

Reported side effects are oral and anogenital candidiasis, vulvovaginitis, eosinophilia, leucopenia, neutropenia, thrombocytopenia, haemolytic anaemia, pancytopenia, agranulocytosis, anaphylaxis, anaphylactoid reaction, hypersensitivity, pulmonary infiltrates, anaphylactoid purpura, polyarthritisnodosa, abnormal thyroid function, brown-black discolouration of the thyroid, anorexia, dizziness, headache, hypaesthesia, paraesthesia, intracranial hypertension, vertigo, Bulging fontanelle, convulsions, sedation, impaired hearing, tinnitus, myocarditis, pericarditis, cough, dyspnoea, bronchospasm, exacerbation of asthma, pulmonary eosinophilia, pneumonitis, diarrhoea, nausea, stomatitis, discolouration of teeth, vomiting, dyspepsia, dysphagia, enamel hypoplasia, enterocolitis, oesophagitis, oesophageal ulceration, glossitis, pancreatitis, pseudomembranous colitis, increased liver enzymes, hepatitis, autoimmune hepatotoxicity, hepatic cholestatis, hepatic failure, hyperbilirubinemia, jaundice, autoimmune hepatitis, alopecia, erythema multiforme, erythema nodosum, fixed drug eruption, hyperpigmentation of the skin, photosensitivity, pruritis, rash, urticaria, vasculitis, angioedema, exfoliative dermatitis, hyperpigmentation of nails, Stevens-Johnson syndrome, toxic epidermal necrolysis, Drug reaction with eosinophilia and systemic symptoms (DRESS), arthralgia, lupus-like syndrome, myalgia, arthritis, bone discolouration, cases of systemic lupus erythematous (SLE), joint stiffness, joint swelling, increased serum urea, acute renal failure, interstitial nephritis, balanitis, fever, etc. In some cases involving these syndromes, death has been reported.

Hyperpigmentation of various body sites including the skin, nails, teeth, oral mucosa, bones, thyroid, eyes (including sclera and conjunctiva), breast milk, lacrimal secretions and perspiration has been reported. This blue/black/grey or muddy-brown discolouration may be localised or diffuse. The most frequently reported site is in the skin. Pigmentation is often reversible on discontinuation of the drug, although it may take several months or may persist in some cases. The generalised muddy-brown skin pigmentation may persist, particularly in areas exposed to the sun.

Toxicity

The oral LD₅₀ in rats is 2380mg/kg and in mice is 3600mg/kg. The intraperitoneal LD₅₀ in rats is 331mg/kg and in mice is 299mg/kg. The subcutaneous LD₅₀ in rats is 1700mg/kg and in mice is 2290mg/kg.

Patients experiencing an overdose may present with dizziness, nausea, and vomiting. In the event of an overdose, discontinue minocycline and treat patients with symptomatic and supportive measures.

Precaution

Breathing difficulties: Cases of breathing difficulties including dyspnoea, bronchospasm, exacerbation of asthma, pulmonary eosinophilia and pneumonitis have been reported with minocycline use. If patients develop breathing difficulties they should seek urgent medical advice and minocycline should be discontinued.

Paediatric population: All tetracyclines form a stable calcium complex in any bone forming tissue. An increase in the fibula growth rate has been observed in premature babies administered oral tetracyclines. Tetracyclines are known to cause a yellow to brown discoloration of the teeth and enamel hypoplasia in the developing child or foetus.

Hepatic impairment: M Plus should be used with caution in patients with hepatic dysfunction or in conjunction with potentially hepatotoxic drugs, including alcohol.

Auto-immune disorders: Rare cases of auto-immune hepatotoxicity and isolated cases of systemic lupus erythematosus (SLE) have been reported. If patients develop signs or symptoms of SLE or hepatotoxicity, minocycline should be discontinued.

Renal impairment: Studies indicate there is no significant drug accumulation in patients with mild to moderate renal impairment when treated with the recommended dosages of minocycline. In cases of severe renal impairment a reduction of dosage and monitoring of renal function may be required.

Cross-sensitivities: Micro-organisms can develop cross resistance to tetracyclines and patients can develop cross sensitivity. M Plus should be discontinued there are signs/symptoms of overgrowth of resistant organisms.

Intracranial hypertension: As with other tetracyclines, bulging fontanelles in infants and benign intracranial hypertension in juveniles and adults have been reported. Presenting features were headache and visual disturbances including blurring of vision, scotoma and diplopia. Permanent vision loss has been reported. Treatment should cease if evidence of raised intracranial pressure develops.

Hyperpigmentation: As with other tetracyclines, minocycline may cause hyperpigmentation at various body sites. Hyperpigmentation may present regardless of dose or duration of therapy but develops more commonly during long term treatment. Patients should be advised to report any unusual pigmentation without delay and minocycline should be discontinued.

Photosensitivity: Tetracyclines are known to cause photosensitivity reactions. Such patients should be warned to avoid direct exposure to natural or artificial sunlight and to discontinue therapy at the first sign of skin discomfort.

Interaction

Anticoagulants: Plasma prothrombin activity is depressed by tetracyclines. Reduced doses of any concomitant anticoagulants may be necessary.
ACE inhibitors, antacids and adsorbants: Tetracyclines bind to di-/tri-valent cations. Absorption from the gastrointestinal tract is impaired by the concomitant administration of iron, calcium, aluminium, magnesium, bismuth and zinc salt (interactions with specified salts, antacids, kaolin, bismuth containing ulcer-healing drugs, quinapril which contains a magnesium carbonate excipient). Dosages should be maximally separated. Absorption of tetracyclines is not significantly impaired by food, milk and milk products.
Diuretics: Diuretics may aggravate nephrotoxicity by volume depletion.
Antibacterials: M Plus should not be used with penicillins.
Ergotamine and ergometrine: There is an increased risk of ergotism.
Oral contraceptives: Both can induce hyperpigmentation.
Retinoids: Administration of isotretinoin should be avoided shortly before, during and shortly after minocycline therapy.

Food Interaction

• Avoid multivalent ions. Separate administration of aluminium, calcium, iron and magnesium containing products from medication by at least 2 hours.
• Take with or without food.

M Plus multivitamins interaction

[Moderate] GENERALLY AVOID: The bioavailability of oral tetracyclines and iron salts may be significantly decreased during concurrent administration.

Therapeutic failure may result.

The proposed mechanism is chelation of tetracyclines by the iron cation, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract.

In ten healthy volunteers, simultaneous oral administration of ferrous sulfate 200 mg and single doses of various tetracyclines (200 mg to 500 mg) resulted in reductions in the serum levels of methacycline and doxycycline by 80% to 90%, oxytetracycline by 50% to 60%, and tetracycline by 40% to 50%.

In another study, 300 mg of ferrous sulfate reduced the absorption of tetracycline by 81% and that of minocycline by 77%.

Conversely, the absorption of iron has been shown to be decreased by up to 78% in healthy subjects and up to 65% in patients with iron depletion when ferrous sulfate 250 mg was administered with tetracycline 500 mg.

Available data suggest that administration of iron 3 hours before or 2 hours after a tetracycline largely prevents the interaction with most tetracyclines except doxycycline.

Due to extensive enterohepatic cycling, iron binding may occur with doxycycline even when it is given parenterally.

It has also been shown that when iron is administered up to 11 hours after doxycycline, serum concentrations of doxycycline may still be reduced by 20% to 45%.

Coadministration of a tetracycline with any iron-containing product should be avoided if possible.

Otherwise, patients should be advised to stagger the times of administration by at least three to four hours, although separating the doses may not prevent the interaction with doxycycline.

M Plus Drug Interaction

Unknown: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, diphenhydramine, diphenhydramine, duloxetine, duloxetine, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, levothyroxine, levothyroxine, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol, alprazolam, alprazolam, cetirizine, cetirizine

M Plus Disease Interaction

Major: colitisModerate: hepatotoxicity, renal dysfunction, esophageal irritation

Volume of Distribution

The volume of distribution of minocycline has been reported as 67.5-115L.

Elimination Route

100mg of oral minocycline reaches a C_max of 1.6mg/L, with a T_max of 1.9h, and an AUC of 31.6mg/L*h. 200mg of oral minocycline reaches a C_max of 3.1mg/L, with a T_max of 2.5h, and an AUC of 48.3mg/L*h.

Half Life

The half life of minocycline pellet filled capsules is 11.1-22.1 hours. M Plus intravenous injections have a half live of 15-23 hours.

Clearance

Intravenous minocycline has a clearance of 3.36-5.7L/h, while oral minocycline has a clearance of 3.42-4.4L/h.

Elimination Route

M Plus is predominantly eliminated through the biliary route. 4.5-9% of an intravenous minocycline dose is recovered in the urine. 10-19.5% of an oral dose is recovered in the urine and 20-34% is recovered in the feces.

Pregnancy & Breastfeeding use

M Plus use during pregnancy and lactation is contraindicated. Animal studies have indicated that tetracyclines cross the placenta. Tetracyclines have been found in foetal tissues and can have toxic effects on the developing foetus (related to retardation of skeletal development). Studies on animals treated during early pregnancy also indicate embryotoxicity. The use of tetracyclines during the last half of pregnancy, when the teeth are developing, may cause permanent discolouration of teeth (more common with long term or repeated short term use). Enamel hypoplasia has also been reported. Tetracyclines have been detected in the milk of lactating women. Permanent tooth discolouration may occur in the developing infant and enamel hypoplasia has been reported.

Contraindication

M Plus is contraindicated in patients with hypersensitivity to tetracyclines, systemic lupus erythematosus, pregnancy, lactation, complete renal failure and children under 12 years.

Acute Overdose

Dizziness, nausea and vomiting are the adverse effects most commonly seen in overdose. Gastric lavage plus appropriate supportive treatment. Antacids and calcium salts will reduce absorption of minocycline but there is no specific antidote. M Plus is not removed in significant quantities by haemodialysis or peritoneal dialysis.

Storage Condition

Store in a cool and dry place, protected from light, store below 25°C.

Innovators Monograph

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