Prescription Drug Information: Sildenafil

SILDENAFIL- sildenafil citrate tablet, film coated
XLCare Pharmaceuticals, Inc.

1 INDICATIONS & USAGE

Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil tablets were added to background epoprostenol therapy [see Clinical Studies (14)].
Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II to III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%).
Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [see Clinical Studies ( 14)].

2 DOSAGE & ADMINISTRATION

2.1 Sildenafil Tablets

The recommended dose of sildenafil tablets is 20 mg three times a day. Administer sildenafil tablet doses 4 to 6 hours apart.
In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended.

3 DOSAGE FORMS & STRENGTHS

White to off white colored, round shaped, biconvex, film coated tablets debossed with ‘J’ on one side and ‘95’ on the other side.

4 CONTRAINDICATIONS

Sildenafil tablets are contraindicated in patients with:
• Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions (5.2)].
• Concomitant use of riociguat, a guanylate cyclase stimulator. PDE-5 inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat.
• Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of
• sildenafil.

5 WARNINGS AND PRECAUTIONS

5.1 Mortality with Pediatric Use

In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil tablets dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients withPAH. Use of sildenafil tablets, particularly chronic use, is not recommended in children [ see Use in Specific Populations (8.4) ].

5.2 Hypotension

Sildenafil tablets have vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil tablets, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil tablets.

5.3 Worsening Pulmonary Vascular Occlusive Disease

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of sildenafil tablets to patients with veno-occlusive disease, administration of sildenafil tablets to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil tablets are administered, consider the possibility of associated PVOD.

5.4 Epistaxis

The incidence of epistaxis was 13% in patients taking sildenafil tablets with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil tablets 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil tablets-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil tablets are unknown in patients with bleeding disorders or active peptic ulceration.

5.5 Visual Loss

When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 males aged ≥ 50 per year in the general population.
An observational case-crossover study evaluated the risk of NAION when PDE-5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE-5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies.
Neither the rare postmarketing reports, nor the association of PDE-5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE-5 inhibitor use and NAION [see Adverse Reactions ( 6.2 ].
Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil tablets. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE-5 inhibitors.
There are no controlled clinical data on the safety or efficacy of sildenafil tablets in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil tablets with caution in these patients.

5.6 Hearing Loss

Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil tablets. In some of the cases, medical conditions and other factors were reported that may have played a role. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil tablets, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors.
Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil tablets.

5.7 Combination with other PDE-5 inhibitors

Sildenafil is also marketed as VIAGRA ®. The safety and efficacy of combinations of sildenafil tablets with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil tablets not to take VIAGRA or other PDE­5 inhibitors.

5.8 Priapism

Use sildenafil tablets with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result.

5.9 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia

In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil tablets than by those randomized to placebo. The effectiveness and safety of sildenafil tablets in the treatment of PAH secondary to sickle cell anemia has not been established.

6 ADVERSE REACTIONS

The following serious adverse events are discussed elsewhere in the labeling:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Safety data of sildenafil tablets in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil tablets-treated patients with PAH, WHO Group I [see Clinical Studies (14)] .
The overall frequency of discontinuation in sildenafil tablets-treated patients on 20 mg three times a day was 3% and was the same for the placebo group.
In Study 1, the adverse reactions that were reported by at least 3% of sildenafil tablets-treated patients (20 mg three times a day) and were more frequent in sildenafil tablets-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature.
Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in Sildenafil Tablets-Treated Patients than Placebo-Treated Patients and Incidence ≥3% in Sildenafil Tablets-Treated Patients)

Placebo, % (n = 70) Sildenafil Tablets 20 mg three times a day, % (n = 69) Placebo- Subtracted, %
Epistaxis 1 9 8
Headache 39 46 7
Dyspepsia 7 13 6
Flushing 4 10 6
Insomnia 1 7 6
Erythema 1 6 5
Dyspnea exacerbated 3 7 4
Rhinitis 0 4 4
Diarrhea 6 9 3
Myalgia 4 7 3
Pyrexia 3 6 3
Gastritis 0 3 3
Sinusitis 0 3 3
Paresthesia 0 3 3

At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision.
The incidence of retinal hemorrhage with sildenafil tablets 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil tablets doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil tablets versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy. In a placebo-controlled fixed dose titration study (Study 2) of sildenafil tablets (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three timesa day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil tablets + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14)] .
Table 2. Adverse Reactions (%) in patients with PAH in Study 2 (incidence in Sildenafil Tablets + Epoprostenol group at least 6% greater than Epoprostenol group)

Sildenafil Tablets+ Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil Tablets+ Epoprostenol) minus Epoprostenol
HeadacheEdema* Dyspepsia Pain in extremity Diarrhea Nausea Nasal congestion 57 25 16 17 25 25 9 34 13 2 6 18 18 2 23 14 14 11 7 7 7

*includes peripheral edema

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