Cefditoren- pivoxil

Cefditoren- pivoxil belongs to the pharmacological class of Third-generation cephalosporin antibiotics.

Cefditoren- pivoxil has been approved to relieve symptoms and also for the treatment and maintenance of Bronchitis,Pneumonia, Tonsillitis/Pharyngitis, Skin or Soft Tissue Infection.

Cefditoren pivoxil is a prodrug that is rapidly hydrolyzed to its active form, cefditoren, after oral administration. Cefditoren is absorbed from the gastrointestinal tract and reaches peak plasma concentrations within 2 hours after administration. The absolute bioavailability of cefditoren pivoxil is approximately 14%, and food delays the time to reach maximum concentration (Tmax) by 1 hour without affecting the extent of absorption (Cmax). Cefditoren has a volume of distribution of approximately 20 L, and it is extensively bound to plasma proteins (approximately 93%). The drug is eliminated primarily unchanged by the kidneys, and the elimination half-life is approximately 1.8 hours in healthy adults with normal renal function.

The common side effects involved in using Cefditoren- pivoxil are Diarrhea, Nausea, Vomiting, Abdominal pain, Headache, Dizziness, Rash, Itching, Elevated liver enzymes

Cefditoren- pivoxil is available in the form of Tablets.

Cefditoren- pivoxil is approved in Germany, Japan, Malaysia, India, U.K.,U.S, and China.

Cefditoren- pivoxil belongs to the pharmacological class of Third-generation cephalosporin antibiotics.

Cefditoren exhibits bactericidal activity by inhibiting cell wall synthesis through its affinity for penicillin-binding proteins (PBPs). It is effective against a range of beta-lactamases, including penicillinases and certain cephalosporinases, and remains stable in their presence.

Cefditoren- pivoxil has been approved to relieve symptoms and also for the treatment and maintenance of Bronchitis,Pneumonia, Tonsillitis/Pharyngitis, Skin or Soft Tissue Infection.

The peak concentration (Cmax) of cefditoren pivoxil in the bloodstream is typically reached within 2 to 3 hours (tmax) after oral administration.

The onset of action is usually within 1 to 2 hours, and the duration of action is approximately 12 hours.

Cefditoren- pivoxil is found to be available in the form of Tablets.

Cefditoren- pivoxil can be used in the following treatment:

• Bronchitis
• Pneumonia
• Tonsillitis/Pharyngitis
• Skin or Soft Tissue Infection

Cefditoren- pivoxil can help to relieve symptoms and also for the treatment and maintenance of Bronchitis, Pneumonia, Tonsillitis/Pharyngitis, Skin or Soft Tissue Infection.

Cefditoren- pivoxil is approved for use in the following clinical indications:

• Bronchitis
• Pneumonia
• Tonsillitis/Pharyngitis
• Skin or Soft Tissue Infection

Adult Dose

• Bronchitis:

400 mg orally twice a day for 10 days for acute bacterial exacerbation of chronic bronchitis.

• Pneumonia:

400 mg orally twice a day for fourteen days for community-acquired pneumonia.

• Tonsillitis/Pharyngitis:

200 mg orally twice a day for ten days.

• Skin or Soft Tissue Infection:

200 mg orally twice a day for ten days for uncomplicated infections.

Pediatric Dose

• Bronchitis:

For patients aged 12 years or older, 400 mg orally twice a day for ten days for acute bacterial exacerbation of chronic bronchitis.

• Pneumonia:

For patients aged 12 years or older, 400 mg orally twice a day for fourteen days for community-acquired pneumonia.

• Tonsillitis/Pharyngitis:

For patients aged 12 years or older, 200 mg orally twice a day for ten days.

• Skin and Structure Infection:

For patients aged 12 years or older, 200 mg orally twice a day for ten days for uncomplicated infections.

Tablets: 200mg, 400mg

Tablets

• Dosage Adjustments in Kidney Patients:

Patients with mild renal impairment (CLcr: 50-80 mL/min/1.73 m2) do not require any dose adjustment. However, patients with moderate renal impairment (CLcr: 30-49 mL/min/1.73 m2) should not be administered more than 200 mg BID, while patients with severe renal impairment (CLcr: <30 mL/min/1.73 m2) should receive 200 mg QD. It is currently unknown what the appropriate dose is for patients with end-stage renal disease.

· Dosage Adjustments in Pediatric Patients:

The safety and efficacy of cefditoren pivoxil tablets has not been established for pediatric patients less than 12 years of age, and its use is not recommended in this population. The potential effects of altered carnitine concentration have also not been studied in this age group.

There are found to be no specific dietary restrictions associated with the use of Cefditoren-pivoxil. However, it is generally recommended to take Cefditoren- pivoxil with food to help increase its absorption and reduce the risk of gastrointestinal side effects such as nausea, vomiting, and diarrhea. It is important to follow any dietary advice provided by your healthcare provider, particularly if you have any underlying medical conditions or take other medications that may interact with Cefditoren-pivoxil. Additionally, it is recommended to avoid alcohol while taking Cefditoren- pivoxil as it may increase the risk of certain side effects.

Cefditoren- pivoxil may be contraindicated under the following conditions:

• In patients who have a known allergy to cephalosporin antibiotics or any of its components.
• Patients with carnitine deficiency or inborn errors of metabolism that can lead to significant carnitine deficiency should not use Cefditoren- pivoxil due to its potential to cause renal excretion of carnitine.
• It is important to note that Cefditoren- pivoxil tablets contain sodium caseinate, a milk protein, and thus should not be administered to patients with hypersensitivity to milk protein (excluding lactose intolerance).

The physician should closely monitor the patients and keep pharmacovigilance as follows:

It is important to carefully inquire about a patient's history of hypersensitivity reactions to cefditoren pivoxil, other cephalosporins, penicillins, or other drugs prior to starting therapy with cefditoren pivoxil. Caution should be exercised when administering cefditoren pivoxil to penicillin-sensitive patients due to the possibility of cross-hypersensitivity among ß-lactam antibiotics, which can occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefditoren pivoxil occurs, the drug is to be discontinued. Serious acute hypersensitivity reactions may require emergency measures, such as treatment with epinephrine, oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, as well as airway management, as clinically indicated.

It is not recommended to prescribe cefditoren pivoxil in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication. Prolonged use of other pivalate-containing compounds has caused clinical manifestations of carnitine deficiency over several months. Therefore, caution should be exercised when using cefditoren pivoxil for prolonged antibiotic treatment. No clinical effects of carnitine decrease had been associated with short-term treatment, but the effects on carnitine concentrations of repeat short-term courses of cefditoren pivoxil are unknown. Although clinical trials have shown no adverse events attributable to decreases in serum carnitine concentrations, some sub-populations, such as patients with renal impairment or decreased muscle mass, might be at increased risk for reductions in serum carnitine concentrations during the cefditoren pivoxil therapy. Furthermore, the appropriate dose for patients with end-stage renal disease has not been determined. As with other antibiotics, prolonged treatment may result in the emergence and overgrowth of resistant organisms, and careful observation of the patient is essential. If superinfection occurs during therapy, appropriate alternative therapy is to be administered.

Cephalosporins might be associated with a fall in prothrombin activity, particularly in patients with renal or hepatic impairment, poor nutritional status, or those receiving prolonged courses of antimicrobial therapy or previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in at-risk patients, and exogenous vitamin K administered as indicated. In clinical trials, there was found to be no difference in the incidence of increased prothrombin time between cefditoren and comparator cephalosporins.

Cefditoren- pivoxil is a cephalosporin antibiotic that may cause certain side effects if taken with alcohol. It is recommended that patients taking Cefditoren- pivoxil should avoid consuming alcohol during treatment. This is because alcohol can increase the risk of certain side effects such as gastrointestinal upset, dizziness, and drowsiness. Alcohol may also reduce the effectiveness of Cefditoren- pivoxil in treating infections.

Cefditoren had been detected in the breast milk of the lactating rats, so caution should be taken when administering the drug to nursing women.

Pregnancy Category B

Cefditoren pivoxil falls under Pregnancy Category B due to its lack of teratogenic effects observed in rats and rabbits at the highest tested doses. In rats, the highest dose administered was 1000 mg/kg/day, equivalent to 24 times the human dose of 200 mg twice a day based on mg/m2/day. Meanwhile, in rabbits, the highest dose administered was 90 mg/kg/day, which is around four times the human dose of 200 mg BID based on mg/m2/day. However, it's worth noting that the highest dose tested in rabbits resulted in severe maternal toxicity, fetal toxicity, and abortions.

Based on a postnatal development study in rats, cefditoren pivoxil didn't show any adverse effects on the postnatal survival, physical as well as behavioral development, learning abilities, as well as reproductive capability at sexual maturity, even when tested at doses of up to 750 mg/kg/day. This dose is approximately 18 times the human dose of 200 mg twide a day based on mg/m2/day. Nonetheless, there are no sufficient and well-controlled studies conducted on pregnant women, so cefditoren pivoxil should only be used during pregnancy if necessary.

There are no specific food warnings related to cefditoren- pivoxil. However, it is recommended to take cefditoren- pivoxil with food to enhance its absorption and reduce the risk of gastrointestinal side effects. It is important to avoid consuming alcohol while taking cefditoren- pivoxil as it may increase the risk of certain side effects such as dizziness and drowsiness.

The adverse reactions related to Cefditoren- pivoxil can be categorized as follows:

Common

• Diarrhea
• Nausea
• Vaginitis
• Abdominal pain
• Headache
• Rash
• Insomnia
• Dizziness
• Vomiting
• Dyspepsia
• Pruritus
• Increased ALT and AST levels
• Increased creatinine levels

Less Common

• Pseudomembranous colitis
• Candidiasis

Rare

• Anaphylaxis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Erythema multiforme
• Agranulocytosis
• Leukopenia
• Thrombocytopenia
• Hemolytic anemia
• Interstitial nephritis
• Seizures
• Clostridium difficile-associated diarrhea
• Hepatic dysfunction
• Cholestatic jaundice
• Hypersensitivity reactions, including serum sickness-like reactions and angioedema.

The clinically relevant drug interactions of Cefditoren- pivoxil is briefly summarized here:

Oral Contraceptives:

The pharmacokinetics of ethinyl estradiol, which is the estrogenic component in most of the oral contraceptives, were not affected by multiple doses of cefditoren pivoxil.

Antacids:

Ethinyl estradiol, which is the estrogenic component in most oral contraceptives, wasn't impacted by repeated doses of cefditoren pivoxil. However, co-administration of cefditoren pivoxil with antacids, specifically those containing magnesium (800 mg) and aluminum (900 mg) hydroxides, resulted in a 14% decrease in mean Cmax and about 11% decrease in mean AUC of cefditoren pivoxil's oral absorption. The clinical significance of this interaction is unknown, so it's not recommended to use antacids with cefditoren pivoxil.

H2-Receptor Antagonists:

Co-administration of cefditoren pivoxil with intravenously administered famotidine (20 mg), an H2 receptor antagonist, led to a 27% decrease in mean Cmax and about 22% decrease in mean AUC of cefditoren pivoxil's oral absorption. It's not recommended to use H2 receptor antagonists with cefditoren pivoxil due to the unknown clinical significance of this interaction.

Probenecid:

probenecid was co-administered with cefditoren pivoxil, the plasma exposure of cefditoren increased. Specifically, there was a 49% increase in mean Cmax, a 122% increase in a mean AUC, and a 53% increase in t1/2, which is consistent with other ß-lactam antibiotics.

The following are the side effects involving Cefditoren-pivoxil:

• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Headache
• Dizziness
• Rash
• Itching
• Elevated liver enzymes

Pregnancy:

Pregnancy Category B

Cefditoren pivoxil falls under Pregnancy Category B due to its lack of teratogenic effects observed in rats and rabbits at the highest tested doses. In rats, the highest dose administered was 1000 mg/kg/day, equivalent to 24 times the human dose of 200 mg twice a day based on mg/m2/day. Meanwhile, in rabbits, the highest dose administered was 90 mg/kg/day, which is around four times the human dose of 200 mg two times a day based on mg/m2/day. However, it's worth noting that the highest dose tested in rabbits resulted in severe maternal toxicity, fetal toxicity, and abortions.

Based on a postnatal development study in rats, cefditoren pivoxil didn't show any adverse effects on postnatal survival, physical as well as behavioral development, learning abilities, as well as reproductive capability at sexual maturity, even when tested at doses of up to about 750 mg/kg/day. This dose is approximately 18 times the human dose of 200 mg two times a day based on mg/m2/day. Nonetheless, there are no sufficient and well-controlled studies conducted on pregnant women, so cefditoren pivoxil should only be used during pregnancy if necessary.

Nursing Mothers:

Cefditoren had been detected in the breast milk of lactating rats, so caution should be taken when administering the drug to nursing women.

Pediatric:

Cefditoren pivoxil has not been recommended for pediatric patients less than 12 years old, and the safety and efficacy of the drug in this population have not been established.

Geriatric:

In clinical studies, 12% of the 2675 patients who received cefditoren pivoxil 200 mg BID were over 65 years of age, while 14% of the 2159 patients who received cefditoren pivoxil 400 mg BID were over 65 years of age. However, no significant differences were observed in terms of safety and effectiveness between older and younger patients. Geriatric patients with normal renal function do not require dose adjustments. It is important to note that cefditoren pivoxil is primarily excreted by the kidney, and therefore, there may be a greater risk of toxic reactions in patients with impaired renal function, particularly in the elderly who are more likely to have decreased renal function. Therefore, caution should be exercised when selecting a dose for elderly patients, and renal function may need to be monitored.

Physicians should be knowledgeable and vigilant about the treatment and identification of overdosage of Cefditoren-pivoxil.

An overdose of Cefditoren- pivoxil may cause symptoms such as abdominal pain, nausea, vomiting, and diarrhea. If an overdose is suspected, immediate medical attention should be sought.

There is no specific antidote for Cefditoren- pivoxil overdose. Treatment is supportive and symptomatic. Gastric lavage or emesis may be considered if the drug has been recently ingested, and activated charcoal may be used to reduce absorption.

Since Cefditoren is primarily eliminated through renal excretion, hemodialysis or peritoneal dialysis may be considered as a treatment option, particularly in patients with severely impaired renal function.

In case of an allergic reaction, such as difficulty breathing, swelling of the face or throat, or rash, emergency medical attention should be sought immediately.

Pharmacodynamics

Cefditoren pivoxil is classified as a prodrug, which means that it is hydrolyzed by esterases during the absorption process. As a result, active cefditoren is distributed throughout the bloodstream. Cefditoren is a cephalosporin that is effective against both gram-positive and gram-negative pathogens. It can be used to treat a variety of bacterial infections, including methicillin-susceptible strains of Staphylococcus aureus (including b-lactamase-producing strains), penicillin-susceptible strains of Staphylococcus aureus and Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae (including b-lactamase-producing strains), Haemophilus parainfluenzae (including b-lactamase-producing strains), Moraxella catarrhalis (including b-lactamase-producing strains), Streptococcus agalactiae, Streptococcus Groups C and G, and Streptococcus viridans group (penicillin-susceptible and -intermediate strains).

Pharmacokinetics

Absorption:

After oral ingestion, cefditoren pivoxil is absorbed from the gastrointestinal tract and transformed to cefditoren by esterases. The estimated absolute bioavailability of the cefditoren pivoxil is around 14% under fasting conditions. However, when cefditoren pivoxil is administered with a low-fat meal (693 cal, 14 g fat, 122 g carb, 23 g protein), the absolute bioavailability is approximately 16.1 ± 3.0%.

Volume of distribution:

The volume of distribution for cefditoren is 9.3 ± 1.6 L.

Protein binding:

According to in vitro studies, the average plasma protein binding for cefditoren is 88%, and it remains concentration-independent at cefditoren concentrations ranging from 0.05 to 10 mg/mL.

Metabolism:

Cefditoren pivoxil is hydrolyzed to cefditoren after ingestion, which produces pivalate. Cefditoren is not significantly metabolized.

Route of elimination:

Renal excretion is the primary elimination route for pivalate, with more than 99% being eliminated as pivaloylcarnitine.

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