Chemical formula: C₈H₁₄N₃O₆P Molecular mass: 279.187 g/mol PubChem compound: 60613
Cidofovir interacts in the following cases:
The safety and efficacy of cidofovir have not been established in patients with hepatic disease and therefore it should be used with caution in this patient population.
There are no studies of cidofovir on the fertility of men or women. Male patients should be advised that cidofovir caused reduced testes weight and hypospermia in animals. Although not observed in clinical studies of cidofovir, such changes may occur in humans and cause infertility.
There is a risk that concomitant treatment of cidofovir with products containing tenofovir disoproxil fumarate may give rise to a pharmacodynamic interaction and increase the risk of Fanconi syndrome.
Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to administration of cidofovir. The safety of cidofovir has not been evaluated in patients receiving other known potentially nephrotoxic agents (e.g. tenofovir, aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, adefovir and vancomycin).
Cidofovir should not be administered concurrently with medicinal products containing tenofovir disoproxil fumarate due to the risk of Fanconi syndrome.
It is recommended to discontinue potentially nephrotoxic agents at least 7 days before starting cidofovir.
Patients treated at 3.0 mg/kg, 5.0 mg/kg or 10 mg/kg without concomitant probenecid developed evidence of proximal tubular cell injury, including glycosuria, and decreases in serum phosphate, uric acid and bicarbonate, and elevations in serum creatinine. The signs of nephrotoxicity were partially reversible in some patients. Concomitant use of probenecid is essential for reducing the pronounced nephrotoxicity of cidofovir to an extent that results in an acceptable benefit/risk balance of cidofovir therapy.
Therapy must be accompanied by administration of oral probenecid and adequate intravenous saline prehydration with each cidofovir dose. All clinical trials relevant to clinical efficacy evaluation were performed using probenecid concomitantly with cidofovir. Two grams of probenecid should be administered 3 hours prior to the cidofovir dose and one gram administered at 2 and again at 8 hours after completion of the 1 hour cidofovir infusion (for a total of 4 grams). In order to reduce the potential for nausea and/or vomiting associated with administration of probenecid, patients should be encouraged to eat food prior to each dose of probenecid. The use of an anti-emetic may be necessary.
In patients who develop allergic or hypersensitivity symptoms to probenecid (e.g., rash, fever, chills and anaphylaxis), prophylactic or therapeutic use of an appropriate antihistamine and/or paracetamol should be considered.
Cidofovir administration is contraindicated in patients unable to receive probenecid because of a clinically significant hypersensitivity to the active substance or medicinal product or to other sulfa containing medicines. Use of cidofovir without concomitant probenecid has not been clinically investigated. A probenecid desensitisation program is not recommended for use.
In addition to probenecid, patients must receive a total of one litre of 0.9% (normal) saline solution intravenously immediately prior to each infusion of cidofovir. Patients who can tolerate the additional fluid load may receive up to a total of 2 litres of 0.9% saline intravenously with each dose of cidofovir. The first litre of saline solution should be infused over a 1 hour period immediately before the cidofovir infusion, and the second litre, if given, infused over a 1-3 hour period beginning simultaneously with the cidofovir infusion or starting immediately after the infusion of cidofovir.
Cidofovir therapy should be discontinued and intravenous hydration is advised if serum creatinine increases by ≥44 μmol/l (≥0.5 mg/dl), or if persistent proteinuria ≥ 2+ develops. In patients exhibiting ≥2+ proteinuria, intravenous hydration should be performed and the test repeated. If following hydration, a ≥2+ proteinuria is still observed, cidofovir therapy should be discontinued. Continued administration of cidofovir to patients with persistent ≥2+ proteinuria following intravenous hydration may result in further evidence of proximal tubular injury, including glycosuria, decreases in serum phosphate, uric acid and bicarbonate, and elevations in serum creatinine.
Interruption, and possibly discontinuation, is required for changes in renal function. For those patients who fully recover from cidofovir associated renal toxicity, the benefits-risk balance of reintroducing cidofovir has not yet been evaluated.
Caution should be applied when considering cidofovir treatment of patients with diabetes mellitus due to the potential increased risk of developing ocular hypotony.
There are no data from the use of cidofovir in pregnant women. Studies in animals have shown reproductive toxicity.
Cidofovir is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is unknown whether cidofovir/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with cidofovir.
Women of childbearing potential have to use effective contraception during and after treatment with cidofovir. Men should be advised to practice barrier contraceptive methods during and for 3 months after treatment with cidofovir.
There are no studies of cidofovir on the fertility of men or women. Male patients should be advised that cidofovir caused reduced testes weight and hypospermia in animals. Although not observed in clinical studies of cidofovir, such changes may occur in humans and cause infertility.
Cidofovir has negligible influence on the ability to drive and use machines. Adverse reactions such as asthenia may occur during cidofovir therapy. The physician is advised to discuss this issue with the patient, and based upon the condition of the disease and the tolerance of medication, give his recommendation in the individual case.
The adverse reactions below are identified through clinical trials or post-marketing surveillance by system organ class (SOC) and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: 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) or not known (cannot be estimated from the available data). Adverse reactions identified from post-marketing experience are included in italics.
Adverse reactions possibly or probably related to cidofovir based on clinical trial experience and post-marketing surveillance:
Very common: Neutropenia
Very common: Headache
Common: Iritis, uveitis, hypotony of the eye
Not known: Hearing impaired
Common: Dyspnea
Very common: Nausea, vomiting
Common: Diarrhoea
Not known: Pancreatitis
Very common: Alopecia, rash
Very common: Proteinuria, blood creatinine increased
Common: Renal failure
Uncommon: Fanconi syndrome acquired
Very common: Asthenia, fever
Common: Chills
Reports of renal failure (plus events possibly caused by renal failure, e.g. blood creatinine increased, proteinuria, glycosuria) received during post-marketing surveillance include some which were fatal. Cases of acute renal failure have been reported after only one or two doses of cidofovir.
The finding of any glycosuria, proteinuria/aminoaciduria, hypouricemia, hypophosphatemia and/or hypokalemia, should prompt for the consideration of cidofovir-related Fanconi syndrome.
The following adverse reactions are possibly or probably related to probenecid based on clinical trial experience:
Common: Headache
Very common: Nausea, vomiting
Very common: Rash
Very common: Fever
Common: Asthenia, chills
In addition probenecid may also cause other adverse reactions including anorexia, gingival pain, flushing, alopecia, dizziness, anaemia, and pollakiuria. Hypersensitivity reactions, with dermatitis, pruritus, urticaria and, rarely, anaphylaxis, and Stevens-Johnson syndrome have occurred. There have been reports of leukopenia, hepatic necrosis, nephrotic syndrome, and aplastic anaemia. Haemolytic anaemia has also occurred, and may be associated with G6DP deficiency. Therefore, when co-prescribing probenecid with cidofovir, it is important for prescribers to consult the current probenecid SmPC (or an appropriate drug reference source) for full information on the safety profile and other features of that product.
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