Triapten

How old is patient? < 1 1-5 6-15 16-29 30-45 46-60 > 60

Triapten uses

• Description
• Virology
• Clinical pharmacology
• Clinical trials
• Indications
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• Administration
• Dosage
• Patient monitoring
• How supplied
• Triapten reviews

WARNING

RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF Triapten. FREQUENT MONITORING OF SERUM CREATININE, WITH DOSE ADJUSTMENT FOR CHANGES IN RENAL FUNCTION, AND ADEQUATE HYDRATION WITH ADMINISTRATION OF Triapten IS IMPERATIVE.

SEIZURES, RELATED TO ALTERATIONS IN PLASMA MINERALS AND ELECTROLYTES, HAVE BEEN ASSOCIATED WITH Triapten TREATMENT. THEREFORE, PATIENTS MUST BE CAREFULLY MONITORED FOR SUCH CHANGES AND THEIR POTENTIAL SEQUELAE. MINERAL AND ELECTROLYTE SUPPLEMENTATION MAY BE REQUIRED.

Triapten IS INDICATED FOR USE ONLY IN IMMUNOCOMPROMISED PATIENTS WITH CMV RETINITIS AND MUCOCUTANEOUS ACYCLOVIR-RESISTANT HSV INFECTIONS..

DESCRIPTION

Triapten is the brand name for Triapten. The chemical name of Triapten is phosphonoformic acid, trisodium salt. Triapten is a white, crystalline powder containing 6 equivalents of water of hydration with an empirical formula of Na₃CO₅P-_{6 H2O and a molecular weight of 300.1. The structural formula is:}

Triapten has the potential to chelate divalent metal ions, such as calcium and magnesium, to form stable coordination compounds. Triapten INJECTION is a sterile, isotonic aqueous solution for intravenous administration only. The solution is clear and colorless. Each milliliter of Triapten contains 24 mg of Triapten hexahydrate in Water for Injection, USP. Hydrochloric acid may have been added to adjust the pH of the solution to 7.4. Triapten INJECTION contains no preservatives.

structural formula

VIROLOGY

Mechanism of Action

Foscarnet exerts its antiviral activity by a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases. Foscarnet does not require activation by thymidine kinase or other kinases.

Antiviral Activity in Cell Culture

The quantitative relationship between the cell culture susceptibility of human cytomegalovirus (CMV) or herpes simplex virus 1 and 2 (HSV-1 and HSV-2) to foscarnet and clinical response to therapy has not been established and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC₅₀), vary greatly depending on the assay method used, cell type employed and the laboratory performing the test. A number of sensitive viruses and their EC₅₀ values are listed below (Table 1). The combination antiviral activity of foscarnet and ganciclovir or acyclovir are not antagonistic in cell culture.

*Mean = 269 μM
Virus	EC50 value (μM)
CMV Ganciclovir resistant CMV HSV-1, HSV-2 HSV-TK negative mutant HSV-DNA polymerase mutants	50-800* 190 10-130 67 5-443

Antiviral Activity in vivo

Statistically significant decreases in positive CMV cultures from blood and urine have been demonstrated in two studies (FOS-03 and ACTG-015/915) of subjects treated with Triapten. Although median time to progression of CMV retinitis was increased in subjects treated with Triapten, reductions in positive blood or urine cultures have not been shown to correlate with clinical efficacy in individual subjects (Table 2).

*A total of 77 subjects were treated with Triapten in two clinical trials (FOS-03 and ACTG-015/915).
Not all subjects had blood or urine cultures done and some subjects had results from both cultures.
†(60 mg/kg Triapten TID for 2–3 weeks).
Blood		+CMV	-CMV
Baseline		27	34
End of Induction†		1	60
Urine		+CMV	-CMV
Baseline		52	6
End of Induction†		21	37

Resistance

Cell culture: CMV and HSV isolates with reduced susceptibility to foscarnet have been selected in cell culture by passage of wild type virus in the presence of increasing concentrations of the drug. All foscarnet resistant isolates are known to be generated through amino acid substitutions in the viral DNA polymerase pUL54 (CMV) or pUL30 (HSV) (Table 3).

CMV pUL54	T419M, T552N, S585A, F595I, Q807A, M844T/V, V946L
HSV-1 pUL30	Y577H, E597D, A605V, L702H, V714M, L774F, L788M, D780N, L782I, P797T, L802F, V813M, V817M, Y818C, T821M, R842S, S889A, F891C, V892M, D907V, A910V, SRA914-916LCV, V958L, R959H
HSV-2 pUL30	_

In vivo: Limited clinical data are available on the development of clinical resistance to foscarnet and many pathways to resistance likely exist. Substitutions documented in the literature in treated patients as associated with foscarnet resistance, are listed in Table 4.

Note: Many additional pathways to foscarnet resistance likely exist
CMV pUL54	N495K, Q578H/L, D588E/N, T700A, V715M, E756D/K/Q, L773V, L776M, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, T838A, G841A/S, del 981-982
HSV-1 pUL30	S599L, D672N, R700G, V715G, A719T/V, S724N, E798K, G841C/S, A910T, Y941H
HSV-2 pUL30	A724T, S725G, S729N, Q732R, L783M, D785N, T844I, L850I, D912V

The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

Cross-Resistance: The amino acid substitutions that resulted in reduced susceptibility to foscarnet and either ganciclovir, acyclovir and/or cidofovir are summarized in Tables 5 and 6.

Cross-resistant to ganciclovir	CMV pUL54	Q578H, D588N, E756K, L773V, L776M, V781I, V787L, L802M, A809V, V812L, T813S, T821I, A834P, G841A/S, del 981-982
Cross-resistant to cidofovir	CMV pUL54	Q578H, D588N, E756K, L773V, V812L, T813S, A834P, G841A, del 981-982

Cross-resistant to acyclovir	HSV-1 pUL30	E597D, S599L, A605V, D672N, R700G, L702H, V714M, V715G, A719T/V, S724N, L774F, L778M, D780N, L782I, P797T, E798K, L802F, V813M, V817M, Y818C, T821M, G841C/S, R842S, S889A, F891C/Y, V892M, D907V, A910V/T, SRA914-916LCV, Y941H, V958L, V959H
	HSV-2 pUL30	A724T, S725G, S729N, Q732R, L783M, D785N, T844I, D912V
Marginally cross-resistant to cidofovir	HSV-1 pUL30	V714M, A719V, S724N, L778M, L802F, Y818C, T821M, G841S
	HSV-2 pUL30	L783M

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetics of foscarnet has been determined after administration as an intermittent intravenous infusion during induction therapy in AIDS patients with CMV retinitis. Observed plasma foscarnet concentrations in four studies are summarized in Table 7:

*Values expressed as mean S.D. (number of subjects studied) for each parameter
†50 mg/kg Q8h for 28 days, samples taken 3 hrs after end of 1 hr infusion (Astra Report 815-04 AC025-1)
‡90 mg/kg Q12hr for 28 days, samples taken 1 hr after end of 2 hr infusion (Hengge et al., 1993)
Parameter	60 mg/kg Q8h	90 mg/kg Q12h
C max at steady-state (μM)	589 ± 192 (24)	623 ± 132 (19)
C trough at steady-state (μM)	114 ± 91 (24)	63 ± 57 (17)
Volume of distribution (L/kg)	0.41 ± 0.13 (12)	0.52 ± 0.20 (18)
Plasma half-life (hr)	4.0 ± 2.0 (24)	3.3 ± 1.4 (18)
Systemic clearance (L/hr)	6.2 ± 2.1 (24)	7.1 ± 2.7 (18)
Renal clearance (L/hr)	5.6 ± 1.9 (5)	6.4 ± 2.5 (13)
CSF: plasma ratio	0.69 ± 0.19 (9) †	0.66 ± 0.11(5) ‡

Distribution

In vitro studies have shown that 14 – 17% of foscarnet is protein bound at plasma drug concentrations of 1 – 1000 μM.

The foscarnet terminal half-life determined by urinary excretion was 87.5 ± 41.8 hours, possibly due to release of foscarnet from bone. Postmortem data on several patients in European clinical trials provide evidence that foscarnet does accumulate in bone in humans; however, the extent to which this occurs has not been determined.

Special Populations

Adults with Impaired Renal Function: The pharmacokinetic properties of foscarnet have been determined in a small group of adult subjects with normal and impaired renal function, as summarized in Table 8:

*Group 1 patients had normal renal function defined as a creatinine clearance of >80 mL/min, Group 2 CrCl was 50 – 80 mL/min, Group 3 CrCl was 25 – 49 mL/min and Group 4 CrCl was 10 – 24 mL/min.
Parameter	Group 1 (N=6)	Group 2 (N=6)	Group 3 (N=6)	Group 4 (N=4)
Creatinine clearance (mL/min)	108 ± 16	68 ± 8	34 ± 9	20 ± 4
Foscarnet CL (mL/min/kg)	2.13 ± 0.71	1.33 ± 0.43	0.46 ± 0.14	0.43 ± 0.26
Foscarnet half-life (hr)	1.93 ± 0.12	3.35 ± 0.87	13.0 ± 4.05	25.3 ± 18.7

Total systemic clearance (CL) of foscarnet decreased and half-life increased with diminishing renal function (as expressed by creatinine clearance). Based on these observations, it is necessary to modify the dosage of foscarnet in patients with renal impairment.

Drug Interaction

The pharmacokinetics of foscarnet and ganciclovir were not altered in 13 patients receiving either concomitant therapy or daily alternating therapy for maintenance of CMV disease.

There is no clinically significant interaction with zidovudine (AZT), or probenecid.

CLINICAL TRIALS

CMV Retinitis

A prospective, randomized, controlled clinical trial was conducted in 24 patients with AIDS and CMV retinitis comparing treatment with Triapten to no treatment. Patients received induction treatment of Triapten, 60 mg/kg every 8 hours for 3 weeks, followed by maintenance treatment with 90 mg/kg/day until retinitis progression (appearance of a new lesion or advancement of the border of a posterior lesion greater than 750 microns in diameter). All diagnoses and determinations of retinitis progression were made from masked reading of retinal photographs. The 13 patients randomized to treatment with Triapten had a significant delay in progression of CMV retinitis compared to untreated controls. Median times to retinitis progression from study entry were 93 days (range 21 – >364) and 22 days (range 7 – 42), respectively.

In another prospective clinical trial of CMV retinitis in patients with AIDS (ACTG-915), 33 patients were treated with two to three weeks of Triapten induction (60 mg/kg TID) and then randomized to either 90 mg/kg/day or 120 mg/kg/day maintenance therapy. The median times from study entry to retinitis progression were not significantly different between the treatment groups, 96 (range 14 – >176) days and 140 (range 16 – >233) days, respectively.

In study ACTG 129/FGCRT SOCA study 107 patients with newly diagnosed CMV retinitis were randomized to treatment with Triapten (induction: 60 mg/kg TID for 2 weeks;

Maintenance: 90 mg/kg QD) and 127 were randomized to treatment with ganciclovir (induction: 5 mg/kg BID;

Maintenance: 5 mg/kg QD). The median time to progression on the two drugs was similar (Fos=59 and Gcv=56 days).

Relapsed CMV Retinitis

The CMV Retinitis Retreatment Trial (ACTG 228/SOCA CRRT) was a randomized, open-label comparison of Triapten or ganciclovir monotherapy to the combination of both drugs for the treatment of persistently active or relapsed CMV retinitis in patients with AIDS. Subjects were randomized to one of the three treatments: Triapten 90 mg/kg BID induction followed by 120 mg/kg QD maintenance (Fos); ganciclovir 5 mg/kg BID induction followed by 10 mg/kg QD maintenance (Gcv); or the combination of the two drugs, consisting of continuation of the subject's current therapy and induction dosing of the other drug (as above), followed by maintenance with Triapten 90 mg/kg QD plus ganciclovir 5 mg/kg QD (Cmb). Assessment of retinitis progression was performed by masked evaluation of retinal photographs. The median times to retinitis progression or death were 39 days for the Triapten group, 61 days for the ganciclovir group and 105 days for the combination group. For the alternative endpoint of retinitis progression (censoring on death), the median times were 39 days for the Triapten group, 61 days for the ganciclovir group and 132 days for the combination group. Due to censoring on death, the latter analysis may overestimate the treatment effect. Treatment modifications due to toxicity were more common in the combination group than in the Triapten or ganciclovir monotherapy groups.

Mucocutaneous Acyclovir Resistant HSV Infections

In a controlled trial, patients with AIDS and mucocutaneous, acyclovir-resistant HSV infection were randomized to either Triapten (N=8) at a dose of 40 mg/kg TID or vidarabine (N=6) at a dose of 15 mg/kg per day. Eleven patients were nonrandomly assigned to receive treatment with Triapten because of prior intolerance to vidarabine. Lesions in the eight patients randomized to Triapten healed after 11 to 25 days; seven of the 11 patients nonrandomly treated with Triapten healed their lesions in 10 to 30 days. Vidarabine was discontinued because of intolerance (N=4) or poor therapeutic response (N=2). In a second trial, forty AIDS patients and three bone marrow transplant recipients with mucocutaneous, acyclovir-resistant HSV infections were randomized to receive Triapten at a dose of either 40 mg/kg BID or 40 mg/kg TID. Fifteen of the 43 patients had healing of their lesions in 11 to 72 days with no difference in response between the two treatment groups.

INDICATIONS

CMV Retinitis

Triapten is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome. Combination therapy with Triapten and ganciclovir is indicated for patients who have relapsed after monotherapy with either drug. SAFETY AND EFFICACY OF Triapten HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (e.g., PNEUMONITIS, GASTROENTERITIS); CONGENITAL OR NEONATAL CMV DISEASE; OR NONIMMUNOCOMPROMISED INDIVIDUALS.

Mucocutaneous Acyclovir Resistant HSV Infections

Triapten is indicated for the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients. SAFETY AND EFFICACY OF Triapten HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER HSV INFECTIONS (e.g., RETINITIS, ENCEPHALITIS); CONGENITAL OR NEONATAL HSV DISEASE; OR HSV IN NONIMMUNOCOMPROMISED INDIVIDUALS.

CONTRAINDICATIONS

Triapten is contraindicated in patients with clinically significant hypersensitivity to Triapten.

WARNINGS

Renal Impairment

THE MAJOR TOXICITY OF Triapten IS RENAL IMPAIRMENT. Renal impairment is most likely to become clinically evident during the second week of induction therapy, but may occur at any time during Triapten treatment. Renal function should be monitored carefully during both induction and maintenance therapy. Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of Triapten. Safety and efficacy data for patients with baseline serum creatinine levels greater than 2.8 mg/dL or measured 24-hour creatinine clearances <50 mL/min are limited.

SINCE Triapten HAS THE POTENTIAL TO CAUSE RENAL IMPAIRMENT, DOSE ADJUSTMENT BASED ON SERUM CREATININE IS NECESSARY. Hydration may reduce the risk of nephrotoxicity. It is recommended that 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of Triapten to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90-120 mg/kg of Triapten, and 500 mL with 40–60 mg/kg of Triapten. Hydration fluid may need to be decreased if clinically warranted.

After the first dose, the hydration fluid should be administered concurrently with each infusion of Triapten.

Mineral and Electrolyte Abnormalities

Triapten has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia. Triapten may also be associated with a dose-related decrease in ionized serum calcium which may not be reflected in total serum calcium. This effect is likely to be related to chelation of divalent metal ions such as calcium by foscarnet. Patients should be advised to report symptoms of low ionized calcium such as perioral tingling, numbness in the extremities and paresthesias. Particular caution and careful management of serum electrolytes is advised in patients with altered calcium or other electrolyte levels before treatment and especially in those with neurologic or cardiac abnormalities and those receiving other drugs known to influence minerals and electrolytes. Physicians should be prepared to treat these abnormalities and their sequelae such as tetany, seizures or cardiac disturbances. The rate of Triapten infusion may also affect the decrease in ionized calcium. Therefore, an infusion pump must be used for administration to prevent rapid intravenous infusion. Slowing the infusion rate may decrease or prevent symptoms.

Seizures

Seizures related to mineral and electrolyte abnormalities have been associated with Triapten treatment. Several cases of seizures were associated with death. Cases of status epilepticus have been reported. Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions.

Hypersensitivity

Serious acute hypersensitivity reactions (e.g., anaphylactic shock, urticaria, angioedema) have been reported postmarketing in patients receiving Triapten. If such an acute reaction occurs, therapy should be discontinued and appropriate medical therapy immediately instituted.

QT prolongation and torsade de pointes

Triapten has been associated with prolongation of the QT interval, an ECG abnormality that has been associated with torsades de pointes, which has been reported during postmarketing surveillance for Triapten. Some of these patients had confounding risk factors such as underlying cardiac disease, electrolyte abnormalities and other concomitant medications.

Use with caution in patients who have a history of QT prolongation, in patients who are taking medications known to prolong the QT interval, in patients with electrolyte disturbances, or in patients who have other risk factors for QT prolongation. Electrocardiograms (ECGs) and measurement of electrolytes should be obtained prior to treatment initiation and periodically during treatment with Triapten.

PRECAUTIONS

General

Care must be taken to infuse solutions containing Triapten only into veins with adequate blood flow to permit rapid dilution and distribution to avoid local irritation. Local irritation and ulcerations of penile epithelium have been reported in male patients receiving Triapten, possibly related to the presence of drug in the urine. Cases of male and female genital irritation/ulceration have been reported in patients receiving Triapten. Adequate hydration with close attention to personal hygiene may minimize the occurrence of such events.

Due to the sodium content of Triapten (240 micromoles (5.5 mg) of sodium per mL), avoid Triapten use when intravenous infusion of a large amount of sodium or water may not be tolerated (e.g. in patients with cardiomyopathy). Triapten should also be avoided in patients on a controlled sodium diet.

Hematopoietic System

Anemia has been reported in 33% of patients receiving Triapten in controlled studies. Granulocytopenia has been reported in 17% of patients receiving Triapten in controlled studies; however, only 1% (2/189) were terminated from these studies because of neutropenia.

Information for Patients

CMV Retinitis: Patients should be advised that Triapten is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during or following treatment. They should be advised to have regular ophthalmologic examinations.

Mucocutaneous Acyclovir-Resistant HSV Infections: Patients should be advised that Triapten is not a cure for HSV infections. While complete healing is possible, relapse occurs in most patients. Because relapse may be due to acyclovir-sensitive HSV, sensitivity testing of the viral isolate is advised. In addition, repeated treatment with Triapten has led to the development of resistance associated with poorer response. In the case of poor therapeutic response, sensitivity testing of the viral isolate also is advised.

Effects on Ability to Drive and Use Machines: Adverse effects such as dizziness and convulsions may occur during Triapten therapy. Patients who experience seizures, dizziness, somnolence or other adverse reactions that could result in impairment, should be advised to avoid driving or operating machinery.

General: Patients should be informed that the major toxicities of foscarnet are renal impairment, electrolyte disturbances, and seizures, and that dose modifications and possibly discontinuation may be required. The importance of close monitoring while on therapy must be emphasized. Patients should be advised of the importance of reporting to their physicians symptoms of perioral tingling, numbness in the extremities or paresthesias during or after infusion as possible symptoms of electrolyte abnormalities. Patients should also be advised to promptly report any cardiac symptoms. Should such symptoms occur, the infusion of Triapten should be stopped, appropriate laboratory samples for assessment of electrolyte concentrations obtained, and a physician consulted before resuming treatment. The rate of infusion must be no more than 1 mg/kg/minute. The potential for renal impairment may be minimized by accompanying Triapten administration with hydration adequate to establish and maintain a diuresis during dosing.

Drug Interactions

A possible drug interaction of Triapten and intravenous pentamidine has been described. Concomitant treatment of four patients in the United Kingdom with Triapten and intravenous pentamidine may have caused hypocalcemia; one patient died with severe hypocalcemia. Toxicity associated with concomitant use of aerosolized pentamidine has not been reported. Because Triapten can reduce serum levels of ionized calcium, extreme caution is advised when used concurrently with other drugs known to influence serum calcium levels. Renal impairment and symptomatic hypocalcemia have been observed during concurrent treatment with Triapten and intravenous pentamidine.

Because of foscarnet's tendency to cause renal impairment, the use of Triapten should be avoided in combination with potentially nephrotoxic drugs such as aminoglycosides, amphotericin B, cyclosporine, acyclovir, methotrexate, tacrolimus and intravenous pentamidine unless the potential benefits outweigh the risks to the patient.

When diuretics are indicated, thiazides are recommended over loop diuretics because the latter inhibit renal tubular secretion, and may impair elimination of Triapten, potentially leading to toxicity.

Abnormal renal function has been observed in clinical practice during the use of Triapten and ritonavir, or Triapten, ritonavir, and saquinavir.

Because of the risk of QT prolongation and the potential for torsades de pointes, the use of Triapten should be avoided in combination with agents known to prolong the QT interval including Class IA (e.g., quinidine or procainamide) or Class III (e.g., dofetilide, amiodarone, sotalol) antiarrhythmic agents, phenothiazines, tricyclic antidepressants, and certain macrolides and fluoroquinolones.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in rats and mice at oral doses of 500 mg/kg/day and 250 mg/kg/day. Oral bioavailability in unfasted rodents is < 20%. No evidence of oncogenicity was reported at plasma drug levels equal to 1/3 and 1/5, respectively, of those in humans (at the maximum recommended human daily dose) as measured by the area-under-the-time/concentration curve (AUC).

Triapten showed genotoxic effects in the BALB/3T3 in vitro transformation assay at concentrations greater than 0.5 mcg/mL and an increased frequency of chromosome aberrations in the sister chromatid exchange assay at 1000 mcg/mL. A high dose of foscarnet (350 mg/kg) caused an increase in micronucleated polychromatic erythrocytes in vivo in mice at doses that produced exposures (area under curve) comparable to that anticipated clinically.

Pregnancy

​There are no adequate and well-controlled studies of Triapten in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Animal Data: Triapten did not adversely affect fertility and general reproductive performance in rats. The results of peri- and post-natal studies in rats were also negative. However, these studies used exposures that are inadequate to define the potential for impairment of fertility at human drug exposure levels.

Daily subcutaneous doses up to 75 mg/kg administered to female rats prior to and during mating, during gestation, and 21 days post-partum caused a slight increase in the number of skeletal anomalies compared with the control group. Daily subcutaneous doses up to 75 mg/kg administered to rabbits and 150 mg/kg administered to rats during gestation caused an increase in the frequency of skeletal anomalies/variations. On the basis of estimated drug exposure (as measured by AUC), the 150 mg/kg dose in rats and 75 mg/kg dose in rabbits were approximately one-eighth (rat) and one-third (rabbit) the estimated maximal daily human exposure. These studies are inadequate to define the potential teratogenicity at levels to which women will be exposed.

Nursing Mothers

It is not known whether Triapten is excreted in human milk; however, in lactating rats administered 75 mg/kg, Triapten was excreted in maternal milk at concentrations three times higher than peak maternal blood concentrations. Because of the potential for serious adverse events in nursing infants, a decision should be made whether to discontinue nursing or discontinue drug, taking into consideration the importance of the drug to the mother. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.

Pediatric Use

The safety and effectiveness of Triapten in pediatric patients have not been established. Triapten is deposited in teeth and bone and deposition is greater in young and growing animals. Triapten has been demonstrated to adversely affect development of tooth enamel in mice and rats. The effects of this deposition on skeletal development have not been studied. Since deposition in human bone has also been shown to occur, it is likely that it does so to a greater degree in developing bone in pediatric patients. Administration to pediatric patients should be undertaken only after careful evaluation and only if the potential benefits for treatment outweigh the risks.

Geriatric Use

No studies of the efficacy or safety of Triapten in persons 65 years of age or older have been conducted. However, Triapten has been used in patients age 65 years of age and older. The pattern of adverse events seen in these patients is consistent across all age groups. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored..

ADVERSE REACTIONS

THE MAJOR TOXICITY OF Triapten IS RENAL IMPAIRMENT. Approximately 33% of 189 patients with AIDS and CMV retinitis who received Triapten (60 mg/kg TID), without adequate hydration, developed significant impairment of renal function (serum creatinine ≥ 2.0 mg/dL). The incidence of renal impairment in subsequent clinical trials in which 1000 mL of normal saline or 5% dextrose solution was given with each infusion of Triapten was 12% (34/280).

Triapten has been associated with changes in serum electrolytes including hypocalcemia (15-30%), hypophosphatemia (8–26%) and hyperphosphatemia (6%), hypomagnesemia (15–30%), and hypokalemia (16–48%). The higher percentages were derived from those patients receiving hydration.

Triapten treatment was associated with seizures in 18/189 (10%) AIDS patients in the initial five controlled studies. Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions predisposing the patient to seizures. The rate of seizures did not increase with duration of treatment. Three cases were associated with overdoses of Triapten.

In five controlled U.S. clinical trials the most frequently reported adverse events in patients with AIDS and CMV retinitis are shown in Table 9. These figures were calculated without reference to drug relationship or severity.

	n = 189		n = 189
Fever	65%	Abnormal Renal Function	27%
Nausea	47%	Vomiting	26%
Anemia	33%	Headache	26%
Diarrhea	30%	Seizures	10%

From the same controlled studies, adverse events categorized by investigator as “severe” are shown in Table 10. Although death was specifically attributed to Triapten in only one case, other complications of Triapten (i.e., renal impairment, electrolyte abnormalities, and seizures) may have contributed to patient deaths.

	n = 189
Death	14%
Abnormal Renal Function	14%
Marrow Suppression	10%
Anemia	9%
Seizures	7%

From the five initial U.S. controlled trials of Triapten, the following list of adverse events has been compiled regardless of causal relationship to Triapten. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medications.

Incidence of 5% or Greater

Body as a Whole: fever, fatigue, rigors, asthenia, malaise, pain, infection, sepsis, death

Central and Peripheral Nervous System: headache, paresthesia, dizziness, involuntary muscle contractions, hypoesthesia, neuropathy, seizures including grand mal seizures

Gastrointestinal System: anorexia, nausea, diarrhea, vomiting, abdominal pain

Hematologic: anemia, granulocytopenia, leukopenia, neutropenia

Metabolic and Nutritional: mineral and electrolyte imbalances including hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia

Psychiatric: depression, confusion, anxiety

Respiratory System: coughing, dyspnea

Skin and Appendages: rash, increased sweating

Urinary: alterations in renal function including increased serum creatinine, decreased creatinine clearance, and abnormal renal function

Special Senses: vision abnormalities

Incidence between 1% and 5%

Application Site: injection site pain, injection site inflammation

Body as a Whole: back pain, chest pain (including reports of transient chest pain as part of infusion reactions), edema, influenza-like symptoms, bacterial infections, moniliasis, fungal infections, abscess

Cardiovascular: hypertension, palpitations, ECG abnormalities including sinus tachycardia, first degree AV block and non-specific ST-T segment changes, hypotension, flushing, cerebrovascular disorder

Central and Peripheral Nervous System: tremor, ataxia, dementia, stupor, generalized spasms, sensory disturbances, meningitis, aphasia, abnormal coordination, leg cramps, EEG abnormalities

Gastrointestinal: constipation, dysphagia, dyspepsia, rectal hemorrhage, dry mouth, melena, flatulence, ulcerative stomatitis, pancreatitis

Hematologic: thrombocytopenia, platelet abnormalities, thrombosis, white blood cell abnormalities, lymphadenopathy

Liver and Biliary: abnormal A-G ratio, abnormal hepatic function, increased SGPT, increased SGOT

Metabolic and Nutritional: hyponatremia, decreased weight, increased alkaline phosphatase, increased LDH, increased BUN, acidosis, cachexia, thirst

Musculo-Skeletal: arthralgia, myalgia

Neoplasms: lymphoma-like disorder, sarcoma

Psychiatric: insomnia, somnolence, nervousness, amnesia, agitation, aggressive reaction, hallucination

Respiratory System: pneumonia, sinusitis, pharyngitis, rhinitis, respiratory disorders, respiratory insufficiency, pulmonary infiltration, stridor, pneumothorax, hemoptysis, bronchospasm

Skin and Appendages: pruritus, skin ulceration, seborrhea, erythematous rash, maculo-papular rash, skin discoloration

Special Senses: taste perversions, eye abnormalities, eye pain, conjunctivitis

Urinary System: albuminuria, dysuria, polyuria, urethral disorder, urinary retention, urinary tract infections, acute renal failure, nocturia, facial edema

Selected adverse events occurring at a rate of less than 1% in the five initial U.S. controlled clinical trials of Triapten include: syndrome of inappropriate antidiuretic hormone secretion, pancytopenia, hematuria, dehydration, hypoproteinemia, increases in amylase and creatinine phosphokinase, cardiac arrest, coma, and other cardiovascular and neurologic complications.

Selected adverse event data from the Foscarnet vs. Ganciclovir CMV Retinitis Trial (FGCRT), performed by the Studies of the Ocular Complications of AIDS (SOCA) Research Group, are shown in Table 11.

* Values for the treatment groups refer only to patients who completed at least one follow-up visit – i.e., 133 to 119 patients in the ganciclovir group and 93 to 100 in the foscarnet group. “Events” denotes all events observed and “patients” the number of patients with one or more of the indicated events.
†Per person-year at risk
‡Final frozen SOCA I database dated October 1991
EVENT	GANCICLOVIR			FOSCARNET
	No. of Events	No. of Patients	Rates†	No. of Events	No. of Patients	Rates†
Absolute neutrophil count decreasing to <0.50 x 109 per liter	63	41	1.30	31	17	0.72
Serum creatinine increasing to >260 μmol per liter (>2.9 mg/dL)	6	4	0.12	13	9	0.30
Seizure ‡	21	13	0.37	19	13	0.37
Catheterization-related infection	49	27	1.26	51	28	1.46
Hospitalization	209	91	4.74	202	75	5.03

Selected adverse events from ACTG Study 228 (CRRT) comparing combination therapy with Triapten or ganciclovir monotherapy are shown in Table 12. The most common reason for a treatment change in patients assigned to either Triapten or ganciclovir was retinitis progression. The most frequent reason for a treatment change in the combination treatment group was toxicity.

* Pts. = patients with event; †Rate = events/person/year; ‡ANC = absolute neutrophil count
	Triapten N=88			Ganciclovir N=93			Combination N=93
	No. Events	No. Pts.*	Rate†	No. Events	No. Pts.*	Rate†	No. Events	No. Pts.*	Rate†
Anemia (Hgb <70g/L)	11	7	0.20	9	7	0.14	19	15	0.33
Neutropenia‡ ANC <0.75 x 109 cells/L ANC <0.50 x 109 cells/L	86 50	32 25	1.53 0.91	95 49	41 28	1.51 0.80	107 50	51 28	1.91 0.85
Thrombocytopenia Platelets <50 x 109/L Platelets <20 x 109/L	28 1	14 1	0.50 0.01	19 6	8 2	0.43 0.05	40 7	15 6	0.56 0.18
Nephrotoxicity Creatinine >260 μmol/L (>2.9 mg/dL)	9	7	0.15	10	7	0.17	11	10	0.20
Seizures	6	6	0.17	7	6	0.15	10	5	0.18
Hospitalizations	86	53	1.86	111	59	2.36	118	64	2.36

Adverse events that have been reported in post-marketing surveillance include: administration site extravasation, localized edema, hypersensitivity reactions (including anaphylactic shock, urticaria and angioedema), gastrointestinal hemorrhage, increased lipase, glomerulonephritis, nephrotic syndrome, proteinuria, status epilepticus, ventricular arrhythmia, prolongation of QT interval, torsade de pointes, gamma GT increased, diabetes insipidus (usually nephrogenic), renal calculus, Fanconi syndrome acquired, renal tubular acidosis, renal tubular necrosis, crystal-induced nephropathy, hypercalcemia, hypernatremia, esophageal ulceration and muscle disorders including myopathy, myositis, muscle weakness and rare cases of rhabdomyolysis. Cases of vesiculobullous eruptions including erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported. In most cases, patients were taking other medications that have been associated with toxic epidermal necrolysis or Stevens-Johnson syndrome.

OVERDOSAGE

In controlled clinical trials performed in the United States, overdosage with Triapten was reported in 10 out of 189 patients. All 10 patients experienced adverse events and all except one made a complete recovery. One patient died after receiving a total daily dose of 12.5 g for three days instead of the intended 10.9 g. The patient suffered a grand mal seizure and became comatose. Three days later the patient expired with the cause of death listed as respiratory/cardiac arrest. The other nine patients received doses ranging from 1.14 times to 8 times their recommended doses with an average of 4 times their recommended doses. Overall, three patients had seizures, three patients had renal function impairment, four patients had paresthesias either in limbs or periorally, and five patients had documented electrolyte disturbances primarily involving calcium and phosphate.

Overdose (up to 20 times the recommended dose) has been reported in post-marketing use of Triapten. Some of these post-marketing reports were relative overdoses in that the dose of Triapten had not been adjusted in patients with a reduced renal function. The pattern of adverse events associated with a Triapten overdose is consistent with the known adverse event profile of the drug.

There is no specific antidote for Triapten overdose. Hemodialysis and hydration may be of benefit in reducing drug plasma levels in patients who receive an overdosage of Triapten, but the effectiveness of these interventions has not been evaluated. The patient should be observed for signs and symptoms of renal impairment and electrolyte imbalance. Medical treatment should be instituted if clinically warranted.

DOSAGE AND ADMINISTRATION

CAUTION-DO NOT ADMINISTER Triapten BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF Triapten MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS. CARE SHOULD BE TAKEN TO AVOID UNINTENTIONAL OVERDOSE BY CAREFULLY CONTROLLING THE RATE OF INFUSION. THEREFORE, AN INFUSION PUMP MUST BE USED. IN SPITE OF THE USE OF AN INFUSION PUMP, OVERDOSES HAVE OCCURRED.

ADMINISTRATION

Instructions for Administration and Preparation

Triapten is administered by controlled intravenous infusion, either by using a central venous line or by using a peripheral vein. The rate of infusion must be no more than 1 mg/kg/minute. An individualized dose of Triapten should be calculated on the basis of body weight, renal function, indication of use and dosing frequency (refer to DOSAGE subsection). To reduce the risk of nephrotoxicity, creatinine clearance (mL/min/kg) should be calculated even if serum creatinine is within the normal range, and doses should be adjusted accordingly.

An individualized dose at the required concentration (24 mg/mL or 12 mg/mL) for the route of administration (central line or peripheral line) needs to be aseptically prepared prior to dispensing. The standard 24 mg/mL solution may be used with or without dilution when using a central venous catheter for infusion. When a peripheral vein catheter is used, the 24 mg/mL injection must be diluted to a 12 mg/mL concentration with 5% dextrose in water or with a normal saline solution prior to administration to avoid local irritation of peripheral veins. Dilutions and/or removals of excess quantities should be accomplished under aseptic conditions. Solutions thus prepared should be used within 24 hours of first entry into a sealed bottle.

Hydration

Hydration may reduce the risk of nephrotoxicity. Clinically dehydrated patients should have their condition corrected before initiating Triapten therapy. It is recommended that 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of Triapten to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90–120 mg/kg of Triapten, and 500 mL with 40–60 mg/kg of Triapten. Hydration fluid may need to be decreased if clinically warranted. Oral rehydration with similar regimens may be considered in certain patients. After the first dose, the hydration fluid should be administered concurrently with each infusion of Triapten.

Compatibility With Other Solutions/Drugs

Other drugs and supplements can be administered to a patient receiving Triapten. However, care must be taken to ensure that Triapten is only administered with normal saline or 5% dextrose solution and that no other drug or supplement is administered concurrently via the same catheter. Foscarnet has been reported to be chemically incompatible with 30% dextrose, amphotericin B, and solutions containing calcium such as Ringer's lactate and TPN. Physical incompatibility with other IV drugs has also been reported including acyclovir sodium, ganciclovir, trimetrexate glucuronate, pentamidine isethionate, vancomycin, trimethoprim/sulfamethoxazole, diazepam, midazolam, digoxin, phenytoin, leucovorin, and proclorperazine. Because of foscarnet's chelating properties, a precipitate can potentially occur when divalent cations are administered concurrently in the same catheter.

Parenteral drug products must be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Solutions that are discolored or contain particulate matter should not be used.

Accidental Exposure

Accidental skin and eye contact with Triapten solution may cause local irritation and burning sensation. If accidental contact occurs, the exposed area should be flushed with water.

DOSAGE

THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATES SHOULD NOT BE EXCEEDED. ALL DOSES MUST BE INDIVIDUALIZED FOR PATIENTS' RENAL FUNCTION.

Induction Treatment

The recommended initial dose of Triapten for patients with normal renal function is:

• For CMV retinitis patients, either 90 mg/kg every twelve hours or 60 mg/kg (minimum one hour infusion) every eight hours over 2-3 weeks depending on clinical response.
• For acyclovir-resistant HSV patients, 40 mg/kg (minimum one hour infusion) either every 8 or 12 hours for 2-3 weeks or until healed.

An infusion pump must be used to control the rate of infusion. Adequate hydration is recommended to establish a diuresis, both prior to and during treatment to minimize renal toxicity, provided there are no clinical contraindications.

Maintenance Treatment

Following induction treatment the recommended maintenance dose of Triapten for CMV retinitis is 90 mg/kg/day to 120 mg/kg/day (individualized for renal function) given as an intravenous infusion over 2 hours. Because the superiority of the 120 mg/kg/day has not been established in controlled trials, and given the likely relationship of higher plasma foscarnet levels to toxicity, it is recommended that most patients be started on maintenance treatment with a dose of 90 mg/kg/day. Escalation to 120 mg/kg/day may be considered should early reinduction be required because of retinitis progression. Some patients who show excellent tolerance to Triapten may benefit from initiation of maintenance treatment at 120 mg/kg/day earlier in their treatment.

An infusion pump must be used to control the rate of infusion with all doses. Again, hydration to establish diuresis both prior to and during treatment is recommended to minimize renal toxicity, provided there are no clinical contraindications.

Patients who experience progression of retinitis while receiving Triapten maintenance therapy may be retreated with the induction and maintenance regimens given above or with a combination of Triapten and ganciclovir. Because of physical incompatibility, Triapten and ganciclovir must NOT be mixed.

Use in Patients with Abnormal Renal Function

Triapten should be used with caution in patients with abnormal renal function because reduced plasma clearance of foscarnet will result in elevated plasma levels. In addition, Triapten has the potential to further impair renal function. Safety and efficacy data for patients with baseline serum creatinine levels greater than 2.8 mg/dL or measured 24-hour creatinine clearances < 50 mL/min are limited.

Renal function must be monitored carefully at baseline and during induction and maintenance therapy with appropriate dose adjustments for Triapten as outlined below. During Triapten therapy if creatinine clearance falls below the limits of the dosing nomograms (0.4 mL/min/kg), Triapten should be discontinued, the patient hydrated, and monitored daily until resolution of renal impairment is ensured.

Triapten is not recommended in patients undergoing hemodialysis because dosage guidelines have not been established.

Dose Adjustment

Triapten dosing must be individualized according to the patient's renal function status. Refer to Table 13 below for recommended doses and adjust the dose as indicated. Even patients with serum creatinine in the normal range may require dose adjustment; therefore, the dose should be calculated at baseline and frequently thereafter.

To use this dosing guide, actual 24-hour creatinine clearance (mL/min) must be divided by body weight (kg), or the estimated creatinine clearance in mL/min/kg can be calculated from serum creatinine (mg/dL) using the following formula (modified Cockcroft and Gault equation):

For males: 140 – age (x 0.85 for females) = mL/min/kg

Serum creatinine x 72

	HSV: Equivalent to		CMV: Equivalent to
CrCI (mL/min/kg)	80 mg/kg/day total (40 mg/kg Q12h)	120 mg/kg/day total (40 mg/kg Q8h)	180 mg/kg/day total
			(60 mg/kg Q8h)	(90 mg/kg Q12h)
>1.4	40 Q12h	40 Q8h	60 Q8h	90 Q12h
>1.0 – 1.4	30 Q12h	30 Q8h	45 Q8h	70 Q12h
> 0.8 – 1.0	20 Q12h	35 Q12h	50 Q12h	50 Q12h
>0.6 – 0.8	35 Q24h	25 Q12h	40 Q12h	80 Q24h
>0.5 – 0.6	25 Q24h	40 Q24h	60 Q24h	60 Q24h
> 0.4 – 0.5	20 Q24h	35 Q24h	50 Q24h	50 Q24h
<0.4	Not recommended	Not recommended	Not recommended	Not recommended

*> means “greater than”, †≥ means “greater than or equal to”, ‡< means “less than”
	CMV: Equivalent to
CrCI (mL/min/kg)	90 mg/kg/day (once daily)	120 mg/kg/day (once daily)
>*1.4	90 Q24h	120 Q24h
>*1.0 – 1.4	70 Q24h	90 Q24h
>*0.8 – 1.0	50 Q24h	65 Q24h
>*0.6 – 0.8	80 Q48h	105 Q48h
>*0.5 – 0.6	60 Q48h	80 Q48h
≥†0.4 – 0.5	50 Q48h	65 Q48h
<‡0.4	Not recommended	Not recommended

PATIENT MONITORING

The majority of patients will experience some decrease in renal function due to Triapten administration. Therefore it is recommended that creatinine clearance, either measured or estimated using the modified Cockcroft and Gault equation based on serum creatinine, be determined at baseline, 2–3 times per week during induction therapy and once weekly during maintenance therapy, with Triapten dose adjusted accordingly. More frequent monitoring may be required for some patients. It is also recommended that a 24-hour creatinine clearance be determined at baseline and periodically thereafter to ensure correct dosing (assuming verification of an adequate collection using creatinine index). Triapten should be discontinued if creatinine clearance drops below 0.4 mL/min/kg.

Due to FOSCAVIR's propensity to chelate divalent metal ions and alter levels of serum electrolytes, patients must be monitored closely for such changes. It is recommended that a schedule similar to that recommended for serum creatinine be used to monitor serum calcium, magnesium, potassium and phosphorus. Particular caution is advised in patients with decreased total serum calcium or other electrolyte levels before treatment, as well as in patients with neurologic or cardiac abnormalities, and in patients receiving other drugs known to influence serum calcium levels. Any clinically significant metabolic changes should be corrected. Also, patients who experience mild (e.g., perioral numbness or paresthesias) or severe (e.g., seizures) symptoms of electrolyte abnormalities should have serum electrolyte and mineral levels assessed as close in time to the event as possible.

Careful monitoring and appropriate management of electrolytes, calcium, magnesium and creatinine are of particular importance in patients with conditions that may predispose them to seizures.

HOW SUPPLIED

Triapten (foscarnet sodium) INJECTION, 24 mg/mL for intravenous infusion, is supplied in 250 mL glass bottles containing 6000 mg Triapten (24 mg/mL) as follows:

NDC 76310-024-25 250 mL bottles, cases of 10

For Single Use Only.

Store between 20° and 25°C (68° and 77°F). Protect from excessive heat (above 40°C) and from freezing. If refrigerated or exposed to temperatures below the freezing point, precipitation may occur. By keeping the bottle at room temperature with repeated shaking, the precipitate can be brought into solution again.

Triapten INJECTION should be used only if the bottle and seal are intact, a vacuum is present, and the solution is clear and colorless.

Manufactured for:

Clinigen Healthcare Ltd., DE14 2WW, UK

By: Fresenius Kabi Austria GmbH, A-8055 Graz, Austria

Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA

Triapten is a trademark of Clinigen Healthcare Ltd.

^© Clinigen Healthcare Ltd., 2017

Date of revision: February 2017

Logos

NDC 76310-024-25

Triapten ^®

(foscarnet sodium) injection

6000 mg/250 mL

(24 mg/mL)

For Central Intravenous Infusion Only

Must Be Diluted for Peripheral Intravenous Infusion

Rx only

For Single Use Only. Discard unused portion.

(Clinigen logo)

Mfd. for: Clinigen Healthcare Ltd., DE14 2WW, UK.

By: Fresenius Kabi Austria GmbH, A-8055 Graz, Austria.

Distributed by: Hospira Inc., Lake Forest, IL 60045 USA.

Triapten is a trademark of Clinigen Healthcare Ltd.

© Clinigen Healthcare Ltd. 2011

(Hospira logo)

NDC 76310-024-25

Triapten ^®

(foscarnet sodium) injection

6000 mg/250 mL

(24 mg/mL)

For Central Intravenous Infusion Only

Must Be Diluted for Peripheral

Intravenous Infusion

Rx only

For Single Use Only. Discard unused portion.

(Clinigen and Hospira logos)

Mfd. for: Clinigen Healthcare Ltd., DE14 2WW, UK.

By: Fresenius Kabi Austria GmbH, A-8055 Graz, Austria.

Distributed by: Hospira Inc., Lake Forest, IL 60045 USA.

Triapten is a trademark of Clinigen Healthcare Ltd.

© Clinigen Healthcare Ltd. 2011

Hospira List No.: 01182-02

CA-2957

Triapten pharmaceutical active ingredients containing related brand and generic drugs:

• Foscarnet Sodium

Triapten available forms, composition, doses:

• N/A

Triapten destination | category:

• Human:
• Antiviral drugs

Triapten Anatomical Therapeutic Chemical codes:

• J05AD01 - Foscarnet

Triapten pharmaceutical companies:

• Riemser Arzneimittel

References

1. Dailymed."FOSCAVIR (FOSCARNET SODIUM) INJECTION, SOLUTION [CLINIGEN HEALTHCARE LTD.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. "foscarnet". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
3. "foscarnet". http://www.drugbank.ca/drugs/DB0052... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Triapten?

Depending on the reaction of the Triapten after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Triapten not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Triapten addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Triapten, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Triapten consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology